Omega-3 pentaenoic acid compositions and methods of use

ABSTRACT

Orally administrable composition comprising fatty acids, wherein at least 50% by weight of the fatty acids comprise omega-3-fatty acids, salts or derivatives thereof, wherein the omega-3 fatty acids comprise eicosapentaenoic acid (EPA; C20:5-n3), docosapentaenoic acid (DPA; C22:5-n3), and docosahexaenoic acid (DHA; C22:6-n3), wherein the ratio of DHA to EPA (DHA:EPA) is less than 1:20, and wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1 are provided. These compositions can be used for the treatment or prophylaxis of dyslipidemic, cardiovascular, CNS, inflammatory, and other diseases/conditions or risk factors therefore.

RELATED APPLICATIONS

This application is a continuation-in-part (CIP) application of PCTInternational Application No. PCT/US13/46176, filed on Jun. 17, 2013,which claims the benefit of U.S. Provisional Patent Application No.61/660,757, filed Jun. 17, 2012, U.S. Provisional Patent Application No.61/734,331, filed Dec. 6, 2012, and U.S. Provisional Patent ApplicationNo. 61/780,948, filed Mar. 13, 2013, the contents of which areincorporated herein by reference.

FIELD OF INVENTION

The present invention relates to a method comprising administeringomega-3 fatty acid compositions for the reduction of fasting lipidparameters, such as triglycerides, total cholesterol, low densitylipoprotein (LDL) cholesterol, free fatty acids, and other lipids. Thepresent invention also relates to a method comprising administration ofomega-3 fatty acid compositions for the increase of high densitylipoprotein (HDL) cholesterol. The methods of the present invention maybe useful of the treatment of a condition selected from the groupconsisting of: hypertriglyceridemia; hypercholesterolemia; mixeddyslipidemia; coronary heart disease (CHD); vascular disease;cardiovascular disease; acute coronary syndrome; atherosclerotic diseaseand related conditions; heart failure; cardiac arrhythmias; coagulatoryconditions associated with cardiac arrhythmias; ischemic dementia;vascular dementia; hypertension; coagulation related disorders;nephropathy; kidney or urinary tract disease; retinopathy; cognitive andother CNS disorders; autoimmune diseases; inflammatory diseases; asthmaor other respiratory disease; dermatological disease; metabolicsyndrome; diabetes, diabetes mellitis or other form of metabolicdisease; liver disease; non-alcoholic fatty liver disease; disease ofthe gastrointestinal tract; disease of the male or female reproductivesystem or related secondary sexual organs; a cancer of any type,including lymphomas and myelomas; an infection caused by a virus,bacterium, fungus, protozoa or other organism; and the treatment and/orprevention and/or reduction of cardiac events and/or cardiovascularevents and/or vascular events and/or symptoms. The present inventionalso relates to treatment of such conditions in with concomitanttreatments regimes or combination products with other activepharmaceutical ingredients.

BACKGROUND OF THE INVENTION

In humans, cholesterol and triglycerides are part of lipoproteincomplexes in the bloodstream, and can be separated viaultracentrifugation into high-density lipoprotein (HDL),intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)and very-low-density lipoprotein (VLDL) fractions. Cholesterol andtriglycerides are synthesized in the liver, incorporated into VLDL, andreleased into the plasma. High levels of total cholesterol (total-C),LDL-cholesterol, and apolipoprotein B (a membrane complex forLDL-cholesterol and VLDL-cholesterol, as well as IDL-cholesterol in rareindividuals suffering from a disorder resulting in significantIDL-cholesterol levels) promote human atherosclerosis; these elevatedlevels are often referred to as hypercholesterolemia. Decreased levelsof HDL-cholesterol and its transport complex, apolipoprotein A, as wellas elevated levels of apolipoprotein C-III and serum triglycerides (TG)are also associated with the development of atherosclerosis. Further,cardiovascular morbidity and mortality in humans can vary directly withthe level of total-C, LDL-cholesterol and TG and inversely with thelevel of HDL-cholesterol. In addition, researchers have found thatnon-HDL-cholesterol is an important indicator of hypertriglyceridemia(elevated triglycerides), vascular disease, atherosclerotic disease andrelated conditions. Therefore, non-HDL-cholesterol and fasting TGreduction has also been specified as a treatment objective in NCEP ATPIII. Fasting TG is commonly used as a key measure for TG in lipidmanagement, because it minimizes the confounding factor of TG recentlyabsorbed from meals, including the high variability of the content ofmeals and high variability of post-meal (post-prandial) spikes in TG. Insome preferred embodiments, we refer to fasting TG levels when we referto triglycerides or TG.

The NCEP ATPIII treatment guidelines identify HMG-CoA reductaseinhibitors (“statins”) as the primary treatment option forhypercholesterolemia. In patients with TG<500 mg/dL, LDL-cholesterol isthe primary treatment parameter. Many patients, however, have increasedLDL-cholesterol combined with high TG and low HDL-cholesterol, acondition also known as mixed dyslipidemia. Patients withhypercholesteremia or mixed dyslipidemia often present with high bloodlevels of LDL-cholesterol (i.e. greater than 190 mg/dl) and TG (i.e.levels of 200 mg/dl or higher). The use of diet and single-drug therapydoes not always decrease LDL-cholesterol and TG adequately enough toreach targeted values in patients with mixed dyslipidemia with orwithout a concomitant increase in triglycerides. In these patients, acombined therapy regimen of a statin and a second anti-dyslipidemicagent is often desired. This second agent has historically been afibrate (i.e. gemfibrozil, bezafibrate, or fenofibrate) or extendedrelease niacin. Over the few years, the use omega-3 fatty acidconcentrates in combination with a statin has been growing rapidly dueto concerns about the lack of outcome benefits with fibrates (i.e. theFIELD study) or extended release niacin (i.e. the AIM-HIGH study). Inpatients with isolated hypertriglyceridemia, the use of omega-3 fattyacid concentrates has also grown versus fibrates and extended releaseniacin.

Marine oils, also commonly referred to as fish oils, are a good sourceof the two main omega-3 fatty acids, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), which have been found to regulate lipidmetabolism. Omega-3 fatty acids have been found to have beneficialeffects on the risk factors for cardiovascular diseases, especially mildhypertension, hypertriglyceridemia and on the coagulation factor VIIphospholipid complex activity. Omega-3 fatty acids lower serumtriglycerides (TG), increase serum HDL-cholesterol, lower systolic anddiastolic blood pressure and the pulse rate, and lower the activity ofthe blood coagulation factor VII-phospholipid complex. Further, omega-3fatty acids seem to be well tolerated, without giving rise to any severeside effects.

The table directly below lists the most common omega-3 fatty acids,including their 3-letter abbreviation code. In this application, the useof any of the 3-letter abbreviations shall refer to the omega-3 fattyacid, unless otherwise indicated (e.g. DPA or DPA 22:5 (n-3) or DPA22:5-n3 or DPA 22:5n3 or DPA-n3, which all refer to the omega-3 isomerof docosapentaenoic acid).

Common Name for Omega-3 Fatty Acid Codified (+abbreviation) Lipid NameChemical Name Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13-hexadecatrienoic acid α-Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-octadecatrienoic acid Stearidonic acid (SDA) 18:4 (n-3)all-cis-6,9,12,15- octadecatetraenoic acid Eicosatrienoic acid (ETE)20:3 (n-3) all-cis-11,14,17- eicosatrienoic acid Eicosatetraenoic acid(ETA) 20:4 (n-3) all-cis-8,11,14,17- eicosatetraenoic acidEicosapentaenoic acid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acid Heneicosapentaenoic acid (HPA) 21:5 (n-3)all-cis-6,9,12,15,18- heneicosapentaenoic acid Docosapentaenoic acid(DPA) or 22:5 (n-3) all-cis-7,10,13,16,19- Clupanodonic aciddocosapentaenoic acid Docosahexaenoic acid (DHA) 22:6 (n-3)all-cis-4,7,10,13,16,19- docosahexaenoic acid Tetracosapentaenoic acid(TPA) 24:5 (n-3) all-cis-9,12,15,18,21- tetracosapentaenoic acidTetracosahexaenoic acid (THA) 24:6 (n-3) all-cis-6,9,12,15,18,21- orNisinic acid tetracosahexaenoic acid

One form of omega-3 fatty acids is a concentrate of omega-3, long chain,polyunsaturated fatty acids from fish oil containing DHA ethyl esters,EPA ethyl esters as well as ethyl esters of other omega-3 fatty acids(described in USP35 for LOVAZA®) and is sold under the trademarksOMACOR® and LOVAZA®. Such a form of omega-3 fatty acid comprises atleast 90% omega-3 fatty acids of which at least 80% EPA+DHA (in a ratioof 1.2:1) and is described, for example, in U.S. Pat. Nos. 5,502,077,5,656,667 and 5,698,594. LOVAZA® (omega-3-acid ethyl esters) isindicated for the treatment of patients with hypertriglyceridemia withTG levels of 500 mg/dL or higher.

Another form of omega-3 fatty acid concentrate is sold under thetrademark EPADEL® ® for the treatment of dyslipidemia. This product isdescribed as 98% EPA ethyl ester in Lancet (Vol. 369; Mar. 31, 2007;1090-1098) reporting on a large outcome study with EPADEL®. EPADEL® isknown to contain less than 1% of any fatty acid other than EPA.

Similar to EPADEL®, another form of omega-3 fatty acid concentrate alsoconsists almost entirely of EPA ethyl ester and is known under itsdevelopmental stage name AMR101 or its trade name VASCEPA®. This productis described in US patent application 2010/0278879 as comprising atleast 95% EPA (typically referred to as 97% or at least 96% in companyreleases and references) and less than 1% of any other fatty acid.AMR101 was previously under development for the treatment ofHuntingdon's Disease but failed in phase III clinical development.Subsequently, AMR101 was entered in a development program forhypertriglyceridemia and mixed dyslipidemia.

Yet another concentrate of omega-3, long chain, polyunsaturated fattyacids from fish oil containing approximately 75% DHA and EPA as freefatty acids is known under its developmental stage name EPANOVA™. Thisproduct is described as comprising approximately 55% EPA and 20% DHA.EPANOVA™ was previously under development for the treatment of Crohn'sDisease but failed in phase III clinical development. Subsequently,EPANOVA™ was entered in a development program for hypertriglyceridemiaand mixed dyslipidemia.

Generally, the bioavailability and therapeutic effect of omega-3 fattyacid compositions is dose dependent, i.e., the higher the dose, thegreater the therapeutic affect and bioavailability. However, the effectof each specific omega-3 fatty acid composition may be different, andtherefore the level of therapeutic effect of one composition at a givendose cannot necessarily be inferred from the level of therapeuticeffects of other omega-3 fatty acid compositions at the same or similardose.

For instance, in the MARINE study, it was found that four 1-gramcapsules of AMR101/VASCEPA® significantly reduced fasting TG in patientswith very high triglycerides (TG>500 mg/dL) (March 2011, ACC posterreporting top-line results of the MARINE study), similar to four 1-gramcapsules of LOVAZA® but in a less potent manner (LOVAZA® prescribinginformation, December 2010). In this same study, AMR101 slightly andnon-significantly changed LDL-C while LOVAZA® shows a large significantincrease in this same population, putting the latter at a disadvantage.Table A directly below compares these profiles.

TABLE A Comparison of therapeutic profile of Lovaza and Vascepa inpatients with very high triglycerides (>500 mg/dL) LOVAZA—4 gram/dayVascepa—4 gram/day Vascepa—2 gram/day % change vs. Placebo p-value %change vs. Placebo p-value % change vs. Placebo p-value TG −51.6 p <0.05 −33.1 p < 0.05 −19.7 p < 0.05 Total-C −8.0 p < 0.05 −16.3 p <0.0001 −6.8 p = 0.0148 LDL-C 49.3 p < 0.05 −2.3 NS 5.2 NS VLDL-C −40.8 p< 0.05 −28.6 p = 0.0002 −15.3 p = .038 Non-HDL-C −10.2 p < 0.05 −17.7 p< 0.0001 −8.1 p = .0182 Apo-B NR −8.5 p = 0.0019 −2.6 NS HDL-C 9.1 p <0.05 −3.6 NS 1.5 NS NR = Not Reported; NS = Not Significant

In another study with AMR101/VASCEPA®, the ANCHOR study, it was foundthat four 1-gram capsules of AMR101 significantly reduced fasting TG inpatients on statin therapy with high triglycerides (TG 200-499 mg/dL),similar to four 1-gram capsules of LOVAZA® but in a less potent manner(Study in table 3, LOVAZA® prescribing information, December 2010). Inthis same study, AMR101 decreased LDL-C at 4 gr/day while LOVAZA® showsa significant LDL-C increase in this same population. AMR101 is alsomore potent than LOVAZA® in reducing non-HDL-cholesterol in thispopulation. Table B directly below compares these profiles.

TABLE B Therapeutic profile comparison of Lovaza and Vascepa in patientson statin with high triglycerides (TG 200-499 mg/dL) LOVAZA—4 gram/dayVascepa—4 gram/day Vascepa—2 gram/day % change vs. Placebo p-value %change vs. Placebo p-value % change vs. Placebo p-value TG −23.2 p <0.0001 −21.5 p < 0.0001 −10.1 p = 0.0005 Total-C −3.1 p < 0.05 NR p <0.0001 NR p = 0.0019 LDL-C 3.5 p = 0.05 −6.3 p = 0.0067 −3.6 NS VLDL-C−20.3 p < 0.05 −24.4 p < 0.0001 −10.5 p = 0.0093 Non-HDL-C −6.8 p <0.0001 −13.6 p < 0.0001 −5.5 p = 0.0054 Apo-B −2.3 p < 0.05 −9.3 p <0.0001 −3.8 p = 0.0170 HDL-C 4.6 p < 0.05 −4.5 p = 0.0013 −2.2 NS NS =Not Significant

The resulting lipid profile of AMR101 versus LOVAZA® in highly similarpatient populations indicates that there are significant benefits ofusing an almost pure EPA oil composition as opposed to an omega-3mixture as in LOVAZA®. These benefits translate into better non-HDL- andLDL-Cholesterol reduction with the pure EPA form, where these benefitsare less or, in the case of the LDL-C effect, the opposite.

The recently released results from Omthera's EVOLVE trial with EPANOVA™in patients with very high triglycerides (TG≧500 mg/dL), described a TGreduction of 31% versus baseline for the 4 gram per day dose and 26%versus baseline for the 2 gram per day dose, with 10% and 8% non-HDLreduction respectively. It appears that the TG-reducing potency ofEPANOVA™ is similar to the potency of AMR101. No data were reported byOmthera on the LDL-C effect in the EVOLVE trial.

The recently released results from Omthera's ESPRIT trial with EPANOVA™,in patients with high triglycerides (TG 200-499 mg/dL) while on statintherapy, described a TG reduction of 21% versus baseline for the 4 gramper day dose and 15% versus baseline for the 2 gram per day dose, with7% and 4% non-HDL reduction respectively. It appears that theTG-reducing potency of EPANOVA™ is similar to the potency of AMR101. Nodata were reported by Omthera on the LDL-C effect in the ESPRIT trial.

From the comparison of LOVAZA® versus AMR101 data, there appears to be abenefit of using pure EPA concentrates for dyslipidemia treatment overomega-3 mixtures with regard to LDL-Cholesterol and non-HDL-cholesteroleffects. With the NCEP ATP III guidelines placing LDL-cholesterol andnon-HDL-cholesterol reduction at the top of the treatment hierarchy forpatients with TG<500 mg/dL, AMR101 is clearly superior to LOVAZA® inthis patient category.

In another example, in the ECLIPSE Study, the bioavailability ofEPANOVA™ is compared to LOVAZA® under high fat meal and low fat mealdosing conditions.

In the ECLIPSE study it is found that EPANOVA™ is significantly morebioavailable than LOVAZA® after single dose administration (fourcapsules of 1 gram for both products), both by Cmax (maximumconcentration) and AUC (area under curve) measures (see Table C below,where Cmax and AUC are estimated from the data points in FIGS. 1 and 2).Relative to LOVAZA® under high fat meal conditions, EPANOVA™ is 1.17×more bioavailable by Cmax and 1.27 by AUC comparison. Under low fat mealconditions, LOVAZA® has only 15% AUC and 12% Cmax of the bioavailabilityversus LOVAZA® under high fat meal conditions, whereas EPANOVA™ underlow fat meal conditions has 78% AUC and 53% Cmax of the bioavailabilityversus LOVAZA® under high fat meal conditions. EPANOVA™ under low fatmeal conditions has 62% AUC and 46% Cmax of the bioavailability versusEPANOVA™ under high fat meal conditions.

TABLE C Comparison of bioavailability of EPA + DHA in Plasma for Lovaza(4 g) and Epanova (4 g) under high-fat and low-fat meal dosingconditions LOVAZA - LOVAZA - Epanova - Epanova - High Fat Low Fat HighFat Low Fat Cmax EPA + DHA 385 nmol/ml 45 nmol/ml 450 nmol/ml 205nmol/ml Est. AUC, 0-24 3080 nmol*hr/ml 465 nmol*hr/ml 3920 nmol*hr/ml2415 nmol*hr/ml EPA + DHA Tmax EPA + DHA 5 hrs 10 hrs 5 hrs 5 hrsMultiple of Lovaza- 1.00 x 0.15 x 1.27 x 0.78 x HF AUC Multiple of LFvs. NA 0.15 x Lovaza- NA x 0.62 x Epanova- HF AUC HF AUC HF AUC Multipleof Lovaza- 1.00 x 0.12 x 1.17 x 0.53 x HF Cmax Multiple of LF vs. NA0.12 x Lovaza- NA x 0.46 x Epanova- HF Cmax HF Cmax HF Cmax Low fatmeal - NA 1.00 x NA   5.19 x AUC vs. Lov. Low fat meal - NA 1.00 x NA  4.56 x Cmax vs. Lov. High fat meal - 1.00 x NA 1.27 x NA AUC vs. Lov.High fat meal - 1.00 x NA 1.17 x NA Cmax vs. Lov.

Omega-3 fatty acids are known to be “essential fatty acids”. There aretwo series of essential fatty acids (EFAs) in humans. They are termed“essential” because they cannot be synthesized de novo in mammals. Thesefatty acids can be interconverted within a series, but the omega-6 (n-6)series cannot be converted to the omega-3 series nor can the omega-3(n-3) series be converted to the omega-6 series in humans. The main EFAsin the diet are linoleic acid of the omega-6 series and alpha-linolenicacid of the omega-3 series. However, to fulfill most of their biologicaleffects these “parent” EFAs must be metabolised to the other longerchain fatty acids. Each fatty acid probably has a specific role in thebody. The scientific literature suggests that particularly important inthe n-6 series are dihomo-gammalinolenic acid (DGLA, 20:3-n6) andarachidonic acid (ARA, 20:4-n6), while particularly important in the n-3series are eicosapentaenoic acid (EPA, 20:5-n3) and docosahexaenoic acid(DHA, 22:6-n3).

U.S. Pat. No. 6,479,544 describes an invention in which it is found thatARA is highly desirable rather than undesirable and it may be helpful toadminister ARA in association with EPA. This invention providespharmaceutical formulations containing eicosapentaenoic acid or anyappropriate derivative (hereinafter collectively referred to as EPA) andarachidonic acid (ARA), as set out in the granted claims for thispatent. ARA may be replaced by one or more of its precursors, DGLA orGLA. In this reference, the ratio of EPA to ARA is preferably between1:1 and 20:1.

Patent application PCT/GB 2004/000242 describes the treatment orprevention of psoriasis with a formulation comprising more than 95% EPAand less than 2% DHA. In another embodiment of this invention the EPA isreplaced with DPA.

Patent application PCT/NL 2006/050291 (WO/2007/058538, GB 0301701.9)describes combinations of indigestible oligosaccharides and long chainpoly-unsaturated fatty acids such as ARA, EPA, DA, and combinationsthereof to improve intestinal barrier integrity, improving barrierfunction, stimulating gut maturation and/or reducing intestinal barrierpermeability.

Lindeborg et al. (Prostag Leukotr Ess, 2013, 88:313-319) discloses astudy evaluating postprandial metabolism of docosapentaenoic acid (DPA)and eicosapentaenoic acid (EPA) in humans.

Holub et al. (Lipids, 2011, 46:399-407) discloses a study assessing theeffect of oral supplementation with docosapentaenoic acid (DPA) onlevels of serum and tissue lipid classes and their fatty acidcompositions in rat liver, heart, and kidney.

Given the highly beneficial efficacy and side-effect profile of omega-3fatty acid concentrates, these compositions are increasingly popular forthe treatment of patients with dyslipidemias. However, with theincreased popularity of omega-3 fatty acid concentrates, there is anunmet medical need for omega-3 fatty acid containing compositions withimproved bioavailability and a more optimal ratio of potency in reducingTG versus the resulting cholesterol profile. Specifically, agents withboth a higher potency than AMR101/EPADEL® and lesser increase in LDL-Cor further decrease in LDL-C and non-HDL-C than LOVAZA® are required.

Fasting triglyceride levels have been found to be correlated with therisk of cardiovascular diseases and conditions. For example, highfasting triglycerides levels have been associated with an increased riskof myocardial infarction. Gaziano et al. (Circulation, 1997;96:2520-2525) discusses fasting triglyceride levels as a risk factor forcoronary heart disease. Love-Osborne et al. (Pediatr Diabetes, 2006:7:205-210) discloses the role of elevated fasting triglyceride levels inthe development of type 2 diabetes mellitus.

All references cited herein are incorporated by reference in theirentirety.

SUMMARY OF THE INVENTION

The present invention provides a composition comprising fatty acids,wherein at least 50% by weight of the fatty acids comprise omega-3-fattyacids, salts, esters, or derivatives thereof, wherein the omega-3 fattyacids comprise eicosapentaenoic acid (EPA; C20:5-n3) anddocosapentaenoic acid (DPA; C22:5-n3), wherein the ratio of DHA to EPA(DHA:EPA) is less than 1:10, and wherein the ratio of DHA to DPA(DHA:DPA) is less than 2:1. In some embodiments, the compositioncomprises additional fatty acids, such as heneicosapentaenoic acid(HPA), arachidonic acid (ARA), and omega-6-docosapentaenoic acid (n-6DPA), tetracosapentaenoic acid (TPA), and/or gamma-linoleic acid (GLA).These compositions can be used for the treatment or prophylaxis ofdyslipidemic, cardiovascular, central nervous system (CNS),inflammatory, and other diseases/conditions or risk factors therefore.These compositions may also be used for the reduction of symptomsassociated with these conditions.

The present invention provides a pharmaceutical composition comprising:eicosapentaenoic acid (EPA) in an amount between about 70% to about 95%of the total amount of fatty acids and docosapentaenoic acid (DPA),wherein the composition comprises no more than 5% docosahexaenoic acid(DHA) of the total amount of fatty acids, and wherein the ratio ofDHA:DPA is 1:1 or lower. The present invention provides compositionscomprise about 80% to about 90%, alternatively about 81% to about 88%,alternatively about 82% to about 88%, alternatively about 83% to about87%, alternatively about 84% to about 86%, alternatively about 85% EPArelative to the total amount of fatty acids present in the composition.% The present invention provides a pharmaceutical composition comprisingeicosapentaenoic acid (EPA) in a daily dosage amount of between about1000 mg to about 5000 mg, and further comprising docosapentaenoic acid(DPA) and docosahexaenoic acid (DHA), wherein the composition comprisesno more than 5% DHA of the total amount of fatty acids, and wherein theratio of DHA:DPA is 1:1 or lower.

The present invention also provides compositions having an improvedprofile versus very high purity EPA compositions which contain lowlevels of omega-6 fatty acids and low levels of omega-3 fatty acidsother than EPA, ETA, HPA, TPA, and DPA.

The present invention provides methods of reducing lipid parameters,such as triglyceride levels, in a subject in need thereof, comprisingadministering to the subject an orally administrable compositioncomprising at least 50% by weight of the fatty acids compriseomega-3-fatty acids, salts, esters, or derivatives thereof, wherein theomega-3 fatty acids comprise eicosapentaenoic acid (EPA; C20:5-n3),docosapentaenoic acid (DPA; C22:5-n3), and docosahexaenoic acid (DHA;C22:6-n3), wherein the ratio of DHA to EPA (DHA:EPA) is less than 1:20,and wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1.

The present invention also provides methods of reducing one or more ofthe following lipid parameter levels from a baseline lipid parameterlevel: triglycerides, apolipoprotein B (apo B), VLDL-cholesterol,apolipoprotein C-III (apo C-III), total cholesterol, and non-HDLcholesterol, comprising administration of any of the compositions of thepresent invention. The present invention also provides methods ofincreasing the following lipid parameter levels from a baseline lipidparameter level: HDL cholesterol and apolipoprotein A-I (apo A-I),comprising administration of any of the compositions of the presentinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the fasting plasma lipid values after seven days of dosing,relating to the study described in Example 35.

FIG. 2 shows the fasting plasma insulin levels after 28 days ofadministration, relating to the study described in Example 35.

FIG. 3 shows the relative liver gene expression following 28 days ofadministration, relating to the study described in Example 35.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an orally administrable compositioncomprising fatty acids, wherein at least 50% by weight of the fattyacids comprise omega-3-fatty acids, salts, esters, or derivativesthereof, wherein the omega-3 fatty acids comprise eicosapentaenoic acid(EPA; C20:5-n3), docosapentaenoic acid (DPA; C22:5-n3), anddocosahexaenoic acid (DHA; C22:6-n3), wherein the ratio of DHA to EPA(DHA:EPA) is less than 1:20, and wherein the ratio of DHA to DPA(DHA:DPA) is less than 2:1.

In some embodiments, the compositions of the present invention compriseat least 50% omega-3 fatty acids, alternatively at least 55%,alternatively at least 60%, alternatively at least 65%, alternatively atleast 70%, alternatively at least 75%, alternatively at least 80%,alternatively at least 85%, alternatively at least 95%, most preferablyat least 90% omega-3 fatty acids of the total amount of fatty acids. Insome embodiments, the composition comprises at least about 92% to about99%, alternatively about 93% to about 98%, alternatively about 94% toabout 98%, omega-3 fatty acids of the total amount of fatty acids.

In other embodiments, EPA and DPA are jointly present in thecompositions of the present invention at between 55% and 100% of totalfatty acids, alternatively between 60% and 100%, alternatively between65% and 100%, alternatively between 70% and 100%, alternatively between75% and 100%, alternatively between 80% and 100%, alternatively between85% and 95%, alternatively between 85% and 97%, alternatively between88% and 95%, alternatively between 88% and 97%, alternatively between90% and 95%, alternatively between 90% and 97% of the total amount offatty acids.

The fatty acids, such as EPA and DPA, may be present in free fatty acidform, or as a salt, ester, or derivative. The fatty acids are preferablycomposed as a triglyceride, an ester (such as an ethyl ester) or freefatty acid. Other forms of the fatty acids which may be useful includesalts, esters of any type, amides, mono-, di- or triglycerides,phospholipids or any other form which can lead to metabolization of thefatty acids (such as EPA and/or DPA), or the incorporation of the fattyacids (such as EPA and/or DPA) into body fluids, tissues or organs.

Omega-3 fatty acids may be grouped by the number of double bondscontained in the fatty acid chain. For instance, hexadecatrienoic acid(HTA), alpha-linolenic acid (ALA) and eicosatrienoic acid (ETE) areomega-3-trienoic acids; stearidonic acid (SDA) and eicosatetraenoic acid(ETA) are omega-3-tetraenoic acids; EPA, heneicosapentaenoic acid (HPA),DPA and tetracosapentaenoic acid (TPA) are omega-3-pentaenoic acids; andDHA and tetracosahexaenoic acid (THA) are omega-3-hexaenoic acids. Insome preferred embodiments, the term omega-3-pentaenoic acids will referto a mixture of at least two omega-3 pentaenoic acids in a ratio of atleast 1:25, more preferably in a ratio of at least 1:50, more preferablyin a ratio of at least 1:75, more preferably in a ratio of at least1:100, more preferably in a ratio of at least 1:125, more preferably ina ratio of at least 1:150, more preferably in a ratio of at least 1:200.In some embodiments, the ratio refers to the ratio of the leastprevalent omega-3 pentaenoic acid in the mixture to the most prevalentomega-3 pentaenoic acid in the mixture.

In some embodiments, the compositions of the present invention compriseEPA, HPA, DPA and TPA, alternatively EPA and DPA, and alternatively thecompositions of the present invention comprise EPA, HPA and DPA.

In some embodiments, the omega-3-pentaenoic acids in the compositions ofthe present invention comprise no more than 99.5% of a singleomega-3-pentaenoic acid, alternatively no more than 99%; alternativelyno more than 98.5%; alternatively no more than 98%; alternatively nomore than 97.5%; alternatively no more than 96%; alternatively no morethan 95%; alternatively no more than 94%; alternatively no more than93%; alternatively no more than 92%; alternatively no more than 91%;alternatively no more than 90%; alternatively no more than 88%;alternatively no more than 85%; alternatively no more than 80%;alternatively no more than 75%; alternatively no more than 70%;alternatively no more than 65%; alternatively no more than 60%;alternatively no more than 55%; alternatively no more than 50%;alternatively no more than 45%; alternatively no more than 40%;alternatively no more than 30%.

In some embodiments, the compositions of the present invention whereinat least 10%, alternatively at least 20%, alternatively at least 25%,alternatively at least 35%, alternatively at least 50%, alternatively atleast 60%, alternatively at least 65%, alternatively at least 70%,alternatively at least 75%, by weight of the fatty acids compriseomega-3-pentaenoic acids, salts, esters, or derivatives thereof.

In some embodiments, the compositions of the present invention compriseat least 0.01% HPA of total fatty acids in the composition,alternatively at least 0.05% HPA, alternatively at least 0.10% HPA,alternatively at least 0.15% HPA, alternatively at least 0.2% HPA,alternatively at least 0.3% HPA, alternatively at least 0.4% HPA,alternatively at least 0.5% HPA, alternatively at least 0.75% HPA,alternatively at least 1% HPA, alternatively at least 1.5% HPA,alternatively at least 2% HPA, alternatively at least 2.5% HPA,alternatively at least 3% HPA, alternatively at least 3.5% HPA,alternatively at least 4% HPA, alternatively at least 4.5% HPA,alternatively at least 5% HPA, alternatively at least 6% HPA,alternatively at least 7% HPA, alternatively the compositions of thepresent invention comprise at least 9% HPA of total fatty acids in thecomposition. In some embodiments, the compositions of the presentinvention comprise no more than 20% HPA of total fatty acids in thecomposition, alternatively no more than 15% HPA, alternatively no morethan 12% HPA, alternatively no more than 10% HPA, alternatively no morethan 8% HPA, alternatively no more than 7% HPA, alternatively no morethan 6% HPA, alternatively no more than 5% HPA, alternatively no morethan 4% HPA, alternatively no more than 3% HPA, alternatively no morethan 2% HPA, alternatively no more than 1.5% HPA, alternatively thecompositions of the present invention comprise at least 1% HPA of totalfatty acids in the composition. In some embodiments, the compositions ofthe present invention comprise 1% to 20% HPA of the total fatty acids inthe composition. In some embodiments, the compositions of the presentinvention comprise about 1% to about 6% HPA, alternatively about 2% toabout 5% HPA, alternatively about 3% to about 4% HPA, relative to thetotal amount of fatty acids in the composition. In some embodiments, thecompositions of the present invention comprise about 10 mg/g to about 50mg/g HPA, alternatively about 15 mg/g to about 45 mg/g, alternativelyabout 20 mg/g to about 40 mg/g, alternatively about 25 mg/g to about 35mg/g, alternatively about 30 mg/g HPA.

In some embodiments, the compositions of the present invention compriseno more than 10% omega-3 fatty acids that are not omega-3-pentaenoicacids, alternatively no more than 9%, alternatively no more than 8%,alternatively no more than 7%, alternatively no more than 6%,alternatively no more than 5%, alternatively no more than 4.5%,alternatively no more than 4%, alternatively no more than 3.5%,alternatively no more than 3%, alternatively no more than 2.5%,alternatively no more than 2%, alternatively no more than 1.5%,alternatively no more than 1.25%, alternatively no more than 1%,alternatively no more than 0.75%, alternatively no more than 0.5%,alternatively no more than 0.4%, alternatively no more than 0.3%,alternatively no more than 0.2%, alternatively the compositions of thepresent invention comprise no more than 0.1% omega-3 fatty acids thatare not omega-3-pentaenoic acids.

In the embodiments of the present invention, the compositions compriseEPA and DPA in an EPA:DPA ratio between 99:1 and 1:99 EPA:DPA,alternatively between 90:1 and 1:90, alternatively between 60:1 and1:60, alternatively between 60:1 and 1:20, alternatively between 60:1and 1:4, alternatively between 40:1 and 1:20, alternatively between 30:1and 1:20, alternatively between 30:1 and 1:10, alternatively between30:1 and 1:5, alternatively between 40:1 and 1:4, alternatively between30:1 and 1:4, alternatively between 30:1 and 1:2, alternatively between30:1 and 1:1, alternatively between 30:1 and 2:1, alternatively between30:1 and 5:1, alternatively between 20:1 and 1:20, alternatively between20:1 and 1:10, alternatively between 20:1 and 1:5, alternatively between20:1 and 1:2, alternatively between 20:1 and 1:1, alternatively between20:1 and 2:1, alternatively between 20:1 and 5:1, alternatively between20:1 and 10:1, alternatively between 20:1 and 10:1, alternativelybetween 30:1 and 10:1, alternatively between 60:1 and 10:1,alternatively comprise EPA and DPA in an EPA:DPA ratio between 40:1 and10:1. In some embodiments, the ratio of EPA:DPA is greater than 1:1,preferably greater than 2:1, and more preferably greater than 5:1. Insome embodiments, the ratio of EPA:DPA is 1:1 to 25:1, preferably 5:1 to20:1, more preferably 8:1 to 15:1, even more preferably 9:1 to 13:1,even more most preferably about 10:1 to 11:1, and most preferably about10:1.

In some embodiments of the present invention, the compositions compriseEPA in an amount between 55% and 95% relative to the total amount offatty acids present in the composition, alternatively between 60% and95%, alternatively between 65% and 95%, alternatively between 70% and95%, alternatively between 75% and 95%, alternatively between 90% and95%, alternatively between 80% and 95%, alternatively between 90% and95%, alternatively between 55% and 90%, alternatively between 60% and90%, alternatively between 65% and 90%, alternatively between 70% and90%, alternatively between 75% and 90%, alternatively between 80% and90%, alternatively between 85% and 90%, alternatively between 55% and92%, alternatively between 60% and 92%, alternatively between 65% and92%, alternatively between 70% and 92%, alternatively between 75% and92%, alternatively between 80% and 92%, alternatively between 85% and92%, alternatively between 55% and 93%, alternatively between 60% and93%, alternatively between 65% and 93%, alternatively between 70% and93%, alternatively between 75% and 93%, alternatively between 80% and93%, alternatively between 85% and 93%, alternatively more than 85%,alternatively more than 85%, alternatively between 85% and 95% EPArelative to the total amount of fatty acids present in the composition.In some embodiments, the compositions comprise about 70% to about 95%,80% to about 90%, alternatively about 81% to about 88%, alternativelyabout 82% to about 88%, alternatively about 83% to about 87%,alternatively about 84% to about 86%, alternatively about 85% EPArelative to the total amount of fatty acids present in the composition.In some embodiments, the compositions comprise about 750 mg/g to about950 mg/g, alternatively about 800 mg/g to about 900 mg/g, alternativelyabout 830 mg/g to about 870 mg/g, alternatively about 840 mg/g to about870 mg/g, alternatively 845 mg/g to about 865 mg/g, alternatively 846mg/g to about 860 mg/g, alternatively 847 mg/g to about 859 mg/g,alternatively about 848 mg/g to about 858 mg/g, alternatively about 849mg/g to about 857 mg/g, alternatively about 850 mg/g to about 856 mg/g,alternatively about 851 mg/g to about 855 mg/g, alternatively about 852mg/g to about 854 mg/g, alternatively about 853 mg/g EPA.

In other embodiments of the present invention, the compositions compriseDPA in an amount between 1% and 99% relative to the total amount offatty acids present in the composition, alternatively between 1% and95%, alternatively alternativelybetween 1% and 90%, alternativelyalternativelybetween 1% and 85%, alternatively between 1% and 80%,alternatively alternativelybetween 1% and 75%, alternatively between 1%and 70%, alternatively between 1% and 65%, alternatively between 1% and60%, alternatively between 1% and 55%, alternatively between 1% and 50%,alternatively between 1% and 45%, alternatively between 1% and 40%,alternatively between 1% and 35%, alternatively between 1% and 30%,alternatively between 1% and 25%, alternatively between 1% and 20%,alternatively between 1% and 15%, alternatively between 1% and 10%,alternatively between 1% and 5%, alternatively between 2% and 99%,alternatively between 2% and 95%, alternatively between 2% and 90%,alternatively between 2% and 85%, alternatively between 2% and 80%,alternatively between 2% and 75%, alternatively between 2% and 70%,alternatively between 2% and 65%, alternatively between 2% and 60%,alternatively between 2% and 55%, alternatively between 2% and 50%,alternatively between 2% and 45%, alternatively between 2% and 40%,alternatively between 2% and 35%, alternatively between 2% and 30%,alternatively between 2% and 25%, alternatively between 2% and 20%,alternatively between 2% and 15%, alternatively between 2% and 10%,alternatively between 2% and 5%, alternatively between 3% and 99%,alternatively between 3% and 95%, alternatively between 3% and 90%,alternatively between 3% and 85%, alternatively between 3% and 80%,alternatively between 3% and 75%, alternatively between 3% and 70%,alternatively between 3% and 65%, alternatively between 3% and 60%,alternatively between 3% and 55%, alternatively between 3% and 50%,alternatively between 3% and 45%, alternatively between 3% and 40%,alternatively between 3% and 35%, alternatively between 3% and 30%,alternatively between 3% and 25%, alternatively between 3% and 20%,alternatively between 3% and 15%, alternatively between 3% and 10%,alternatively between 3% and 5%, alternatively between 4% and 99%,alternatively between 4% and 95%, alternatively between 4% and 90%,alternatively between 4% and 85%, alternatively between 4% and 80%,alternatively between 4% and 75%, alternatively between 4% and 70%,alternatively between 4% and 65%, alternatively between 4% and 60%,alternatively between 4% and 55%, alternatively between 4% and 50%,alternatively between 4% and 45%, alternatively between 4% and 40%,alternatively between 4% and 35%, alternatively between 4% and 30%,alternatively between 4% and 25%, alternatively between 4% and 20%,alternatively between 4% and 15%, alternatively between 4% and 10%,alternatively between 4% and 5%, alternatively between 5% and 99%,alternatively between 5% and 95%, alternatively between 5% and 90%,alternatively between 5% and 85%, alternatively between 5% and 80%,alternatively between 5% and 75%, alternatively between 5% and 70%,alternatively between 5% and 65%, alternatively between 5% and 60%,alternatively between 5% and 55%, alternatively between 5% and 50%,alternatively between 5% and 45%, alternatively between 5% and 40%,alternatively between 5% and 35%, alternatively between 5% and 30%,alternatively between 5% and 25%, alternatively between 5% and 20%,alternatively between 5% and 15%, alternatively between 5% and 12%,alternatively between 5% and 10%, alternatively between 6% and 99%,alternatively between 6% and 95%, alternatively between 6% and 90%,alternatively between 6% and 85%, alternatively between 6% and 80%,alternatively between 6% and 75%, alternatively between 6% and 70%,alternatively between 6% and 65%, alternatively between 6% and 60%,alternatively between 6% and 55%, alternatively between 6% and 50%,alternatively between 6% and 45%, alternatively between 6% and 40%,alternatively between 6% and 35%, alternatively between 6% and 30%,alternatively between 6% and 25%, alternatively between 6% and 20%,alternatively between 6% and 15%, alternatively between 6% and 12%,alternatively between 6% and 11%, alternatively between 6% and 10%,alternatively between 7% and 99%, alternatively between 7% and 95%,alternatively between 7% and 90%, alternatively between 7% and 85%,alternatively between 7% and 80%, alternatively between 7% and 75%,alternatively between 7% and 70%, alternatively between 7% and 65%,alternatively between 7% and 60%, alternatively between 7% and 55%,alternatively between 7% and 50%, alternatively between 7% and 45%,alternatively between 7% and 40%, alternatively between 7% and 35%,alternatively between 7% and 30%, alternatively between 7% and 25%,alternatively between 7% and 20%, alternatively between 7% and 15%,alternatively between 7% and 12%, alternatively between 7% and 11%,alternatively between 7% and 10%, alternatively between 8% and 99%,alternatively between 8% and 95%, alternatively between 8% and 90%,alternatively between 8% and 85%, alternatively between 8% and 80%,alternatively between 8% and 75%, alternatively between 8% and 70%,alternatively between 8% and 65%, alternatively between 8% and 60%,alternatively between 8% and 55%, alternatively between 8% and 50%,alternatively between 8% and 45%, alternatively between 8% and 40%,alternatively between 8% and 35%, alternatively between 8% and 30%,alternatively between 8% and 25%, alternatively between 8% and 20%,alternatively between 8% and 15%, alternatively between 8% and 12%,alternatively between 9% and 95%, alternatively between 9% and 90%,alternatively between 9% and 85%, alternatively between 9% and 80%,alternatively between 9% and 75%, alternatively between 9% and 70%,alternatively between 9% and 65%, alternatively between 9% and 60%,alternatively between 9% and 55%, alternatively between 9% and 50%,alternatively between 9% and 45%, alternatively between 9% and 40%,alternatively between 9% and 35%, alternatively between 9% and 30%,alternatively between 9% and 25%, alternatively between 9% and 20%,alternatively between 9% and 15%, alternatively between 9% and 12%,relative to the total amount of fatty acids present in the composition.In some embodiments, the compositions comprise DPA in an amount betweenabout 5% to about 15%, alternatively about 6% to about 12%,alternatively about 7% to about 11%, alternatively about 8% to about 10%relative to the total amount of fatty acids present in the composition.In some embodiments, the compositions comprise DPA in an amount of about60 mg/g to about 120 mg/g, alternatively about 70 mg/g to about 100mg/g, 75 mg/g to about 90 mg/g, alternatively about 77 mg/g to about 85mg/g, alternatively about 78 mg/g to about 84 mg/g, alternatively about79 mg/g to about 83 mg/g, alternatively about 80 mg/g to about 82 mg/g,alternatively about 81 mg/g to about 82 mg/g of DPA.

In some embodiments, a relatively small amount of DHA as compared to EPAis present. In some embodiments, the compositions of the presentinvention comprise no more than 1:5 of DHA:EPA, alternatively no morethan 1:6 of DHA:EPA, alternatively no more than 1:7 of DHA:EPA,alternatively no more than 1:8 of DHA:EPA, alternatively no more than1:9 of DHA:EPA, alternatively no more than 1:10 of DHA:EPA,alternatively no more than 1:12 of DHA:EPA, alternatively no more than1:15 of DHA:EPA, alternatively no more than 1:20 of DHA:EPA,alternatively no more than 1:25 of DHA:EPA, alternatively no more than1:30 of DHA:EPA, alternatively no more than 1:40 of DHA:EPA,alternatively no more than 1:50 of DHA:EPA, alternatively no more than1:75 of DHA:EPA, alternatively no more than 1:90 of DHA:EPA,alternatively no more than 1:99 of DHA:EPA. Alternatively, DHA may bepresent in the compositions of this invention at a relative amount ofratio less than 1% than the amount of EPA. Alternatively, DHA may bepresent in the compositions of this invention at a DHA:EPA ratio of lessthan 1:99.

In some embodiments, a relatively small amount of DHA relative to thetotal amount of fatty acids present in the composition is present. Insome embodiments, the compositions of the present invention comprise nomore than 20% DHA, alternatively no more than 15% DHA, alternatively nomore than 12% DHA, alternatively no more than 10% DHA, alternatively nomore than 8% DHA, alternatively no more than 7% DHA, alternatively nomore than 6% DHA, alternatively no more than 5% DHA, alternatively nomore than 4% DHA, alternatively no more than 3% DHA, alternatively nomore than 2% DHA, alternatively no more than 1% DHA relative to thetotal amount of fatty acids present in the composition. In someembodiments, the composition comprises about 5 mg/g to about 20 mg/g,alternatively about 8 mg/g to about 18 mg/g, alternatively about 9 mg/gto about 15 mg/g, alternatively about 10 mg/g to about 14 mg/g,alternatively about 11 mg/g to about 13 mg/g, alternatively about 12mg/g to about 13 mg/g of DHA.

In some embodiments, the ratio of EPA:HPA is about 1500:1 to 25:1,alternatively 1000:1 to 50:1, alternatively 800:1 to 60:1, alternatively500:1 to 60:1, alternatively 250:1 to 75:1, and alternatively 100:1 to80:1. In some preferred embodiments, the ratio of EPA:HPA is about 85:1.In some preferred embodiments, the ratio of EPA:HPA is about 30:1. Insome embodiments, the ratio of DPA:HPA is about 250:1 to 1:1,alternatively 200:1 to 2:1, alternatively 150:1 to 3:1, alternatively100:1 to 4:1, alternatively 50:1 to 5:1, alternatively 25:1 to 6:1, andalternatively 10:1 to 7:1. In some preferred embodiments, the ratio ofDPA:HPA is about 8:1. In some embodiments, the ratio of DPA:HPA is about3:0.

In other embodiments, a relatively small amount of DHA as compared toDPA is present. In these embodiments, the compositions of the presentinvention comprise no more than 15:1 of DHA:DPA, alternatively no morethan 12:1 of DHA:DPA, alternatively no more than 10:1 of DHA:DPA,alternatively no more than 8:1 of DHA:DPA, alternatively no more than5:1 of DHA:DPA, alternatively no more than 3:1 of DHA:DPA, alternativelyno more than 2:1 of DHA:DPA, alternatively no more than 1:1 of DHA:DPA,alternatively no more than 1:2 of DHA:DPA, alternatively no more than1:3 of DHA:DPA, alternatively no more than 1:5 of DHA:DPA, alternativelyno more than 1:8 of DHA:DPA, alternatively no more than 1:10 of DHA:DPA,alternatively no more than 1:15 of DHA:DPA, alternatively no more than1:20 of DHA:DPA, alternatively no more than 1:25 of DHA:DPA,alternatively no more than 1:50 of DHA:DPA, alternatively no more than1:75 of DHA:DPA, alternatively no more than 1:90 of DHA:DPA,alternatively no more than 1:95 of DHA:DPA, alternatively no more than1:100 of DHA:DPA. In some embodiments, the ratio of DHA:DPA ispreferably less than 2:1.

In other embodiments, a relatively small amount of DHA as compared toHPA is present. In these embodiments, the compositions of the presentinvention comprise no more than 15:1 of DHA:HPA, alternatively no morethan 12:1 of DHA:HPA, alternatively no more than 10:1 of DHA:HPA,alternatively no more than 8:1 of DHA:HPA, alternatively no more than5:1 of DHA:HPA, alternatively no more than 3:1 of DHA:HPA, alternativelyno more than 2:1 of DHA:HPA, alternatively no more than 1:1 of DHA:HPA,alternatively no more than 1:2 of DHA:HPA, alternatively no more than1:3 of DHA:HPA, alternatively no more than 1:5 of DHA:HPA, alternativelyno more than 1:8 of DHA:HPA, alternatively no more than 1:10 of DHA:HPA,alternatively no more than 1:15 of DHA:HPA, alternatively no more than1:20 of DHA:HPA, alternatively no more than 1:25 of DHA:HPA,alternatively no more than 1:50 of DHA:HPA, alternatively no more than1:75 of DHA:HPA, alternatively no more than 1:90 of DHA:HPA,alternatively no more than 1:95 of DHA:HPA, alternatively no more than1:100 of DHA:HPA.

In yet other embodiments, the compositions of the present inventioncomprise no more than 10% omega-6 fatty acids relative to the totalamount of fatty acids, alternatively no more than 9%, alternatively nomore than 8%, alternatively no more than 7%, alternatively no more than6%, alternatively no more than 5%, alternatively no more than 4.5%,alternatively no more than 4%, alternatively no more than 3.5%,alternatively no more than 3%, alternatively no more than 2.5%,alternatively no more than 2%, alternatively no more than 1.7%,alternatively no more than 1.5%, alternatively no more than 1.2%,alternatively no more than 1%, alternatively no more than 0.5% omega-6fatty acids versus the total amount of fatty acids comprised by thecompositions of the present invention.

Omega-6 fatty acids include, but are not limited to: linoleic acid (LA;C18:2-n6); gamma-linoleic acid (GLA; C18:3-n6); eicosadienoic acid(C20:2-n6); dihomo-gamma-linoleic acid (DGLA; C20:3-n6); arachiconicacid (ARA; C20:4-n6); and omega-6 docosapentaenoic acid (DPA; C22:5-n6).

In further embodiments, the compositions of the present inventioncomprise no more than 10% omega-6 fatty acids relative to the totalamount of omega-3 fatty acids plus omega-6 fatty acids, alternatively nomore than 9%, alternatively no more than 8%, alternatively no more than7%, alternatively no more than 6%, alternatively no more than 5%,alternatively no more than 4.5%, alternatively no more than 4%,alternatively no more than 3.5%, alternatively no more than 3%,alternatively no more than 2.5%, alternatively no more than 2%,alternatively no more than 1.7%, alternatively no more than 1.5%,alternatively no more than 1.2%, alternatively no more than 1%,alternatively no more than 0.5% omega-6 fatty acids versus the totalamount of omega-3 fatty acids plus omega-6 fatty acids comprised by thecompositions of the present invention.

In yet other embodiments, the compositions of the present inventioncomprise no more than 8% arachidonic acid (ARA; C20:4-n6) relative tothe total amount of omega-3 fatty acids plus omega-6 fatty acids,alternatively no more than 7%, alternatively no more than 6%,alternatively no more than 5%, alternatively no more than 4.5%,alternatively no more than 4%, alternatively no more than 3.5%,alternatively no more than 3%, alternatively no more than 2.5%,alternatively no more than 2%, alternatively no more than 1.7%,alternatively no more than 1.5%, alternatively no more than 1.2%,alternatively no more than 1%, alternatively no more than 0.5%arachidonic acid (ARA; C20:4-n6) versus the total amount of omega-3fatty acids plus omega-6 fatty acids comprised by the compositions ofthe present invention.

In some embodiments, a relatively small amount of omega-3 fatty acids inaggregate other than EPA, ETA, HPA and DPA (alternatively indicated asnon-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids in aggregate)relative to the total amount of fatty acids present in the compositionis present. In some embodiments, the compositions of the presentinvention comprise no more than 20% non-EPA, non-ETA, non-HPA andnon-DPA omega-3 fatty acids, alternatively no more than 15% non-EPA,non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no morethan 12% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids,alternatively no more than 10% non-EPA, non-ETA, non-HPA and non-DPAomega-3 fatty acids, alternatively no more than 8% non-EPA, non-ETA,non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 7%non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternativelyno more than 6% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fattyacids, alternatively no more than 5% non-EPA, non-ETA, non-HPA andnon-DPA omega-3 fatty acids, alternatively no more than 4% non-EPA,non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no morethan 3% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids,alternatively no more than 2% non-EPA, non-ETA, non-HPA and non-DPAomega-3 fatty acids, alternatively no more than 1% non-EPA, non-ETA,non-HPA and non-DPA omega-3 fatty acids in aggregate relative to thetotal amount of fatty acids present in the composition.

In some embodiments, a relatively small amount of the sum of ALA, SDAand DHA relative to the total amount of fatty acids present in thecomposition is present, while at the same time large amounts of the sumof EPA, DPA-n3, HPA and ETA are present. In some embodiments, thecompositions of the present invention comprise no more than 20% of thesum of ALA, SDA and DHA, alternatively no more than 15% of the sum ofALA, SDA and DHA, alternatively no more than 12% of the sum of ALA, SDAand DHA, alternatively no more than 10% of the sum of ALA, SDA and DHA,alternatively no more than 8% of the sum of ALA, SDA and DHA,alternatively no more than 7% of the sum of ALA, SDA and DHA,alternatively no more than 6% of the sum of ALA, SDA and DHA,alternatively no more than 5% of the sum of ALA, SDA and DHA,alternatively no more than 4% of the sum of ALA, SDA and DHA,alternatively no more than 3% of the sum of ALA, SDA and DHA,alternatively no more than 2% of the sum of ALA, SDA and DHA,alternatively no more than 1% of the sum of ALA, SDA and DHA relative tothe total amount of fatty acids present in the composition, while at thesame time contain more than 40% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 50% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 60% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 70% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 75% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 80% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 85% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 90% the sum of EPA, DPAn-3, HPA and ETA,alternatively more than 95% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 80% and 98% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 80% and 96% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 85% and 98% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 85% and 96% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 90% and 98% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 90% and 97% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 90% and 96% the sum of EPA, DPAn-3, HPA and ETA,alternatively between 90% and 95% the sum of EPA, DPAn-3, HPA and ETA,relative to the total amount of fatty acids present in the compositionis present.

In further embodiments, the compositions of the present inventioncomprise no more than 8% arachidonic acid (ARA; C20:4-n6) relative tothe total amount of fatty acids, alternatively no more than 7%,alternatively no more than 6%, alternatively no more than 5%,alternatively no more than 4.5%, alternatively no more than 4%,alternatively no more than 3.5%, alternatively no more than 3%,alternatively no more than 2.5%, alternatively no more than 2%,alternatively no more than 1.7%, alternatively no more than 1.5%,alternatively no more than 1.2%, alternatively no more than 1%,alternatively no more than 0.5% arachidonic acid (ARA; C20:4-n6)relative the total amount of fatty acids comprised by the compositionsof the present invention.

In other embodiments, the compositions of the present invention compriseno more than 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.4%omega-6-docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.2%gamma-linoleic acid (GLA; C18:3-n6) relative the total amount of fattyacids comprised by the compositions of the present invention.

Further embodiments provide fatty acid compositions comprising no morethan 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.3% omega-6docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.1%gamma-linoleic acid (GLA; C18:3-n6) relative the total amount of fattyacids comprised by the compositions of the present invention.

In yet other embodiments, the active ingredient of the formulations ofthe present invention consists essentially wholly of the EPA and DPA orprecursors thereof (ethyl ester, triglyceride, or any otherpharmaceutically acceptable salt or derivative thereof). In that case,no large amounts (preferably less than 15%, alternatively less than 12%,alternatively less than 10%, alternatively less than 9%, alternativelyless than 8%, alternatively less than 7%, alternatively less than 6%,alternatively less than 5%, alternatively less than 4%, alternativelyless than 3%, alternatively less than 2%, alternatively less than 1%,alternatively less than 0.5%, alternatively less than 0.25%) of anyother fatty acids are present.

In further embodiments, the active ingredient of the formulations of thepresent invention consists essentially wholly of omega-3-pentaenoicacids or precursors thereof (ethyl ester, triglyceride, or any otherpharmaceutically acceptable salt or derivative thereof). In that case,no large amounts (preferably less than 15%, alternatively less than 12%,alternatively less than 10%, alternatively less than 9%, alternativelyless than 4%, alternatively less than 4%, alternatively less than 4%,alternatively less than 4%, alternatively less than 4%, alternativelyless than 3%, alternatively less than 2%, alternatively less than 1%,alternatively less than 0.5%, alternatively less than 0.25%) of anyother fatty acids are present.

The fatty acid percentage is determined on a weight/weight, mol/mol, orchromatography area percent basis relative to all fatty acids present inthe composition as determined by methods such as disclosed in theEuropean Pharmacopeia monograph for omega-3 fatty acid concentrates,European Pharmacopeia monograph for omega-3-acid ethyl esters 90%, orEuropean Pharmacopeia monograph method 2.4.29, USP monograph for fishoil dietary supplements, USP 35 omega-3-acid ethyl esters (LOVAZA®)monograph, or any essentially equivalent methods (whether by gaschromatography, HPLC, FPLC or any other chromatographic method).

In some embodiments, the fatty acid percentage is determined not as apercentage of all fatty acids present in the composition but as aspecific type of fatty acid ethyl esters as percentage of all fatty acidethyl esters present in the composition, thus excluding from the fattyacid percentage determination such fatty acids present as, for instance:free fatty acids; mono-, di-, and tri-glycerides; or fatty acids presentin phospholipids (such as phosphatidylserine or phosphatidylcholine) orpolysorbates (such as Tween 80, Tween 20, or polysorbate 40).

In other embodiments, the fatty acid percentage is determined not as apercentage of all fatty acids present in the composition but as aspecific type of free fatty acid as percentage of all free fatty acidspresent in the composition, thus excluding from the fatty acidpercentage determination such fatty acids present as, for instance:fatty acid ethyl esters; mono-, di-, and tri-glycerides; or fatty acidspresent in phospholipids (such as phosphatidylserine orphosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, orpolysorbate 40).

In yet other embodiments, the fatty acid percentage is determined not asa percentage of all fatty acids present in the composition but as aspecific type of glycerol fatty acid ester as percentage of all glycerolfatty acid esters present in the composition, thus excluding from thefatty acid percentage determination such fatty acids present as, forinstance: fatty acid ethyl esters; free fatty acids; or fatty acidspresent in phospholipids (such as phosphatidylserine orphosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, orpolysorbate 40).

In further embodiments, the fatty acid percentage is determined not as apercentage of all fatty acids present in the composition but as di- ortri-fatty acid esters with glycerol as percentage of all glycerol di-and tri-fatty acid esters present in the composition, thus excludingfrom the fatty acid percentage determination such fatty acids presentas, for instance: glycerol-mono-fatty acid esters; fatty acid ethylesters; free fatty acids; or fatty acids present in phospholipids (suchas phosphatidylserine or phosphatidylcholine) or polysorbates (such asTween 80, Tween 20, or polysorbate 40).

In yet other embodiments, the fatty acid percentage is determined not asa percentage of all fatty acids present in the composition but as atri-fatty acid esters with glycerol as percentage of all glyceroltri-fatty acid esters present in the composition, thus excluding fromthe fatty acid percentage determination such fatty acids present as, forinstance: mono- and di-fatty acid esters of glycerol; fatty acid ethylesters; free fatty acids; or fatty acids present in phospholipids (suchas phosphatidylserine or phosphatidylcholine) or polysorbates (such asTween 80, Tween 20, or polysorbate 40).

The EPA, HPA, DPA, or omega-3-pentaenoic acids may be derived from anyappropriate source including plant seed oils, microbial oils from algaeor fungal or marine oils from fish or other marine animals. Certainspecies are a particular good source of oils containing DPA, for exampleseal oil. They may be used in the form of the natural oil, if that oilmeets the required purity requirements of the present invention, or maybe purified to give products containing the fatty acid composition ofthe present invention.

The compositions of the present invention may be produced through arange of the methods. Such methods may include: distillation, includingshort path distillation; urea precipitation; enzymatic conversionconcentration; conventional chromatography; HPLC/FPLC; supercriticalcarbondioxide extraction; supercritical carbondioxide chromatography;simulated moving bed chromatography; supercritical carbondioxidesimulated moving bed chromatography; or chemical conversion methods suchas iodolactonization. Such methods are generally known to those skilledin the art of purifying and isolating omega-3 fatty acids.

Typically, the omega-3 fatty acid concentration/purification process isinitiated by esterifying the fatty acids comprised by the marine oil rawmaterial (such as crude fish oil) with ethanol (to form fatty acid ethylesters) in order to separate omega-3 fatty acids from other fatty acidscovalently bound together in the natural triglyceride molecules of thesource oil. Subsequently, the material may be distilled once or severaltimes to achieve omega-3-acid ethyl ester concentrations above 60%-70%.Alternatively, enzymatic concentration, urea precipitation orsupercritical extraction may be used alone or in conjunction withdistillation to reach omega-3 levels above 70%-90%. In order to preparea highly pure concentrate of a single omega-3 fatty acid, methods suchas chromatography, supercritical chromatography, simulated moving bedchromatography, supercritical simulated moving bed chromatography, orchemical conversion methods such as iodolactolization are typically mostpractical to reach levels above 50%, alternatively above 60%,alternatively above 70%, alternatively above 80%, alternatively above90%, alternatively above 95%, of a single omega-3 fatty acid such asETA, EPA, HPA, DPA, TPA, or DHA.

Those skilled in the art will be able to design processes suited toprepare a certain omega-3 fatty acid composition as desired, based onthe methods described above. Such processes are flexible enough toaffect the relative proportions between the long chain C18, C20, C21 andC22 fatty acids which occur naturally in available fish oil rawmaterials and other marine oils. It provides not only for theconcentration of the individual omega-3 fatty acids, but the ratiobetween them will remain within a pattern of variation caused byvariations in nature. However, suitable methods compensate for sometimesextreme variations which may occur naturally. Thus, for those skilled inthe art, it will be possible to make a product with a constant andpredetermined composition.

EPA is relatively abundant in fish oils or other marine oils and can berelatively easy obtained through the application of concentration andpurification technologies from such fish or marine oils. DPA and HPA arepresent at much lower concentrations. In order to prepare thecompositions of the present invention, DPA or HPA may be concentratedand purified from fish or other marine oils according to the methodsreferred to above, either alone or DPA combined with EPA and/or HPA.Alternatively, the DPA or HPA may be chemically prepared from a highpurity EPA concentrate by elongation of the EPA fatty-acid chain withtwo or one hydrogen-saturated carbons (C2-elongation or C1-elongation)on the carboxyl side of the molecule (for instance with a method similarto or alternate methods with equivalent results such as described byKuklev D V and Smith W L in Chem Phys Lipids, 2006; 144(2): 172-177). Inanother alternative approach, a high purity EPA concentrate may bepartially converted to DPA (or HPA) using a method for C2-elongation (orC1-elongation) of EPA similar to those described above, thus directlyyielding compositions of the present invention or intermediatestherefore.

Once the oils containing one or more of the desired fatty acids havebeen obtained, and purified as necessary, these oils may be blended togive the desirable relative amounts of EPA, DPA, HPA, DHA, TPA, otheromega-3 fatty acids and omega-6 fatty acids to obtain the compositionsof the present invention described in detail above.

Fish oils may also contain by-products and contaminants such aspesticides, chlorinated or brominated hydrocarbons, heavy metals,cholesterol and vitamins. During the production of the concentrate, theconcentrations of these components are significantly reduced compared tountreated fish oils. Such reduction is inherent due to the nature ofpurification methods and their ability to concentrate of several orspecific omega-3 fatty acids, thus removing other compounds.

Triglycerides comprising more than 60% of the omega-3 fatty acids in thecomposition may be produced from ethyl esters and glycerol by wellknown, published, or alternative chemical synthetic or enzymaticprocedures. The free acids may be produced from ethyl esters by wellknown hydrolization or saponification procedures. Methods for convertingethyl esters to triglycerides, free fatty acids, and other molecularforms comprising fatty acids, are generally known to those skilled inthe art chemically or enzymatically converting omega-3 fatty acids fromone form to another.

In some embodiments, the compositions of the present invention haveimproved pharmacological features as demonstrated by improvedbioavailability in a mammal of EPA, HPA, DPA, DHA, EPA+DHA, EPA+DPA orEPA+HPA+DPA combined, total omega-3-pentaenoic acids, or of totalomega-3 fatty acids. Key parameters for determining bioavailability aremaximum concentration of a therapeutic compound or a metabolite thereof(Cmax); the time from administration to maximum concentration (Tmax);and the area under the concentration curve over time (AUC). Suchparameters may be determined under single dose or multiple doseadministration regimens. Methods to determine comparativebioavailability in mammals are generally known to those skilled in theart. When comparing Tmax, Cmax, and AUC for embodiments of the presentinvention to LOVAZA®, EPANOVA™, and AMR101 throughout this application,such comparison will be on the basis of an equal dose of 4 capsules of 1gram each for each of these products. The comparative parameters,however, do apply to all essentially equivalent dosing modes comparingembodiments of the present invention to LOVAZA®, EPANOVA™, and AMR101.

Meal conditions during administration to a subject of omega-3 fatty acidcompositions or omega-3 fatty acid formulations are of specialsignificance for absorption and bioavailability of omega-3 fatty acids.The meal conditions typically considered are: fasting (no food at allprior for 8-12 hours prior to administration and 2-3 hours postadministration of the treatment); a low fat meat (a meal typicallycontaining less than 25 gram of fat [350-600 Kcal] consumed just beforeor after the administration of the treatment; typically within a 15-30minute range); or a high fat meat (a meal containing 40 gram to 75 gramof fat [700-1000 Kcal] consumed just before or after the administrationof the treatment; typically within a 15-30 minute range).

In some embodiments of the present invention, compositions of thepresent invention are more rapidly absorbed as measured by the time toreach the maximum concentration (Tmax) in blood, serum or plasma of EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids. In preferred embodiments of the present invention,Tmax under high fat meal administration conditions is less than 8 hours,alternatively less than 6 hours, alternatively approximately 5 hours,alternatively 4 hours or less. In other preferred embodiments of thepresent invention, Tmax under low fat meal administration conditions isless than 8 hours, alternatively less than 6 hours, alternativelyapproximately 5 hours, alternatively 4 hours or less. In yet otherpreferred embodiments of the present invention, Tmax under fastingadministration conditions is less than 8 hours, alternatively less than6 hours, alternatively approximately 5 hours, alternatively 4 hours orless. In further embodiments of the present invention, Tmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, or total omega-3 fatty acids are equal orless than than Tmax for LOVAZA® for EPA, DPA, DHA, EPA+DPA, EPA+DHA, ortotal omega-3 fatty acids under high fat meat, low fat meal, and fastingadministration conditions. In other embodiments of the presentinvention, Tmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, or total omega-3fatty acids are less than Tmax for LOVAZA® for EPA, DPA, DHA, EPA+DPA,EPA+DHA, or total omega-3 fatty acids under either low fat meal,fasting, or both administration conditions.

In yet other embodiments of the present invention, Tmax for EPA, DPA,DHA, EPA+DPA, EPA+DHA, or total omega-3 fatty acids are equal or lessthan than Tmax for AMR101 for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids under high fatmeat, low fat meal, and fasting administration conditions. Finally, inother embodiments of the present invention, Tmax for EPA, DPA, DHA,EPA+DPA, EPA+DHA, or total omega-3 fatty acids are less than Tmax forAMR101 for EPA+DHA and to EPA, DPA, DHA, EPA+DPA, EPA+DHA, or totalomega-3 fatty acids under either low fat meal, fasting, or bothadministration conditions.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than LOVAZA® as measured by themaximum concentration (Cmax) in blood, serum or plasma of EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids.

In preferred embodiments of the present invention, Cmax for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids under high fat meal administration conditions are preferablyat least 1.1×(110% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®,alternatively at least 1.2×(120% of), alternatively at least 1.3×(130%of), alternatively at least 1.4×(140% of), alternatively at least1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®.

In other preferred embodiments of the present invention, Cmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably at least 1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor LOVAZA®, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of) Cmax for EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids for LOVAZA®.

In other preferred embodiments of the present invention, Cmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under fasting administration conditions arepreferably at least 1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor LOVAZA®, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of), alternatively at least7×(700% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than LOVAZA® as measured by thearea under the concentration curve over time (AUC) in blood, serum orplasma of EPA, DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoicacids, or total omega-3 fatty acids.

In preferred embodiments of the present invention, AUC for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids under high fat meal administration conditions are preferablyat least 1.1×(110% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®,alternatively at least 1.2×(120% of), alternatively at least 1.3×(130%of), alternatively at least 1.4×(140% of), alternatively at least1.5×(150% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably at least 1.5×(150% of) AUC for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor LOVAZA®, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of) AUC for EPA, DPA, DHA,EPA+DPA, EPA+DHA, or total omega-3-pentaenoic acids, or total omega-3fatty acids for LOVAZA®.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under fasting administration conditions arepreferably at least 1.5×(150% of) AUC for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor LOVAZA®, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of), alternatively at least7×(700% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for LOVAZA®.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than AMR101 as measured by themaximum concentration (Cmax) in blood, serum or plasma of EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids.

In preferred embodiments of the present invention, Cmax for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids under high fat meal administration conditions are preferablyat least 1.1×(110% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for AMR101,alternatively at least 1.2×(120% of), alternatively at least 1.3×(130%of), alternatively at least 1.4×(140% of), alternatively at least1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for AMR101.

In other preferred embodiments of the present invention, Cmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably at least 1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor AMR101, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of) Cmax for EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids for AMR101.

In other preferred embodiments of the present invention, Cmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under fasting administration conditions arepreferably at least 1.5×(150% of) Cmax for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor AMR101, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of), alternatively at least7×(700% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for AMR101.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than AMR101 as measured by thearea under the concentration curve over time (AUC) in blood, serum orplasma of EPA, DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoicacids, or total omega-3 fatty acids. In preferred embodiments of thepresent invention, AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids under high fatmeal administration conditions are preferably at least 1.1×(110% of) AUCfor EPA, DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, ortotal omega-3 fatty acids for AMR101, alternatively at least 1.2×(120%of), alternatively at least 1.3×(130% of), alternatively at least1.4×(140% of), alternatively at least 1.5×(150% of) AUC for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids for AMR101.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably at least 1.5×(150% of) AUC for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor AMR101, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of) AUC for EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids for AMR101.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under fasting administration conditions arepreferably at least 1.5×(150% of) AUC for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor AMR101, alternatively at least 2×(200% of), alternatively at least3×(300% of), alternatively at least 4×(400% of), alternatively at least5×(500% of), alternatively at least 6×(600% of), alternatively at least7×(700% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for AMR101.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than EPANOVA™ as measured by themaximum concentration (Cmax) in blood, serum or plasma of EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids.

In preferred embodiments of the present invention, Cmax for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids under high fat meal administration conditions are preferablyapproximately 1.0×(100% of) Cmax (or non-significant difference) forEPA, DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, ortotal omega-3 fatty acids for EPANOVA™ alternatively at least 1.05×(105%of), alternatively at least 1.1×(110% of), alternatively at least1.2×(120% of), alternatively at least 1.3×(130% of) Cmax for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids for EPANOVA™.

In other preferred embodiments of the present invention, Cmax for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably approximately 1.0×(100% of) Cmax (or non-significantdifference) for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™,alternatively at least 1.05×(105% of), alternatively at least 1.1×(110%of), alternatively at least 1.2×(120% of), alternatively at least1.3×(130% of) Cmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™.

In other preferred embodiments of the present invention, Cmax forEPA+DHA, total omega-3-pentaenoic acids, and total omega-3 fatty acidsunder fasting administration conditions are preferably approximately1.0×(100% of) Cmax (or non-significant difference) for EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids for EPANOVA™, alternatively at least 1.05×(105% of), alternativelyat least 1.1×(110% of), alternatively at least 1.2×(120% of),alternatively at least 1.3×(130% of) Cmax for EPA, DPA, DHA, EPA+DPA,EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acidsfor EPANOVA™.

In other embodiments of the present invention, compositions of thepresent invention are better absorbed than EPANOVA™ as measured by thearea under the concentration curve over time (AUC) in blood, serum orplasma of EPA, DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoicacids, or total omega-3 fatty acids.

In preferred embodiments of the present invention, AUC for EPA, DPA,DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3fatty acids under high fat meal administration conditions are preferablyapproximately 1.0×(100% of) AUC (or non-significant difference) for EPA,DPA, DHA, EPA+DPA, EPA+DHA, or total omega-3-pentaenoic acids, or totalomega-3 fatty acids for EPANOVA™, alternatively at least 1.05×(105% of),alternatively at least 1.1×(110% of), alternatively at least 1.2×(120%of), alternatively at least 1.3×(130% of) AUC for EPA, DPA, DHA,EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fattyacids for EPANOVA™.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under low fat meal administration conditions arepreferably approximately 1.0×(100% of) AUC (or non-significantdifference) for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™,alternatively at least 1.05×(105% of), alternatively at least 1.1×(110%of), alternatively at least 1.2×(120% of), alternatively at least1.3×(130% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™.

In other preferred embodiments of the present invention, AUC for EPA,DPA, DHA, EPA+DPA, EPA+DHA, total omega-3-pentaenoic acids, or totalomega-3 fatty acids under fasting administration conditions arepreferably approximately 1.0×(100% of) AUC (or non-significantdifference) for EPA, DPA, DHA, EPA+DPA, EPA+DHA, or totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™alternatively at least 1.05×(105% of), alternatively at least 1.1×(110%of), alternatively at least 1.2×(120% of), alternatively at least1.3×(130% of) AUC for EPA, DPA, DHA, EPA+DPA, EPA+DHA, totalomega-3-pentaenoic acids, or total omega-3 fatty acids for EPANOVA™.

In some embodiments, the improved bioavailability features describedabove are apparent upon single dose administration, while in otherembodiments the improved bioavailability features described above areapparent after multiple dose administration of formulations according tothe present invention as compared to referenced comparator productsabove or substantial equivalent forms thereof.

The compositions of the present invention may be used for the treatmentof patients by administering an effective amount of such compositions toa subject in need thereof, such as a subject prone to or afflicted witha disease or condition or in need of treatment for a disease orcondition. The present invention provides methods of treating,preventing, and reducing symptoms associated with a disease or conditioncomprising administration of a composition of the present invention.Exemplary diseases or conditions include, but are not limited to:hypertriglyceridemia (for example, by those skilled in the art typicallyestablished by assessing fasting triglyceride (TG) levels);hypertriglyceridemia with TG≧500 mg/dL (VHTG); hypertriglyceridemia withTG 200-499 mg/dL; hypertriglyceridemia with TG 200-499 mg/dL while onstatin treatment (HTG); hypercholesterolemia; mixed dyslipidemia;coronary heart disease (CHD); vascular disease; atherosclerotic diseaseand related conditions; heart failure; cardiac arrhythmias; bloodcoagulatory conditions associated with cardiac arrhythmias;hypertension; coagulation related disorders, including post-surgicaldeep vein thrombosis or other high risk thrombosis conditions;nephropathy; kidney or urinary tract disease; retinopathy; cognitive,psychiatric, neurological and other CNS disorders, including but notlimited to schizophrenia, depression, bipolar disorder and any form ofdementia (including ischemic dementia and vascular dementia); autoimmunediseases; inflammatory diseases; asthma, COPD or other respiratorydisease; dermatological disease; metabolic syndrome; diabetes or otherforms of metabolic disease; liver diseases including fatty liverdisease; diseases affecting the senses, including those affecting visionand hearing; diseases of the gastrointestinal tract; diseases of themale or female reproductive system or related secondary sexual organs; acancer of any type, including lymphomas, myelomas and solid tumorcancers; any infections caused by a virus, bacterium, fungus, protozoaor other organism. The present invention also provides for the treatmentand/or prevention of cardiac events and/or cardiovascular events and/orvascular events and/or symptoms. The present invention also provides forthe reduction of number of such events, as well as a reduction oramelioration of symptoms associated with such events.

Cardiovascular and/or cardiac events may include, but are not limitedto: myocardial infarction, ischemic cardiac attack, ischemic attack,acute angina, hospitalization due to acute angina, stroke, transientischemic cerebral attack, cardiac revascularization, cardiacrevascularization with stent placement, carotid arteryrevascularization, carotid artery revascularization with stentplacement, peripheral artery revascularization, peripheral arteryrevascularization with stent placement, plaque rupture, death due tocardiovascular event, and hospitalization due to cardiovascular event.Cardiovascular and/or cardiac events may also include other eventsdeemed to fall in such category by those skilled in the art.

The present invention also provides method for increasinghigh-lipoprotein (HDL) cholesterol levels. The methods related to lipidparameters measured in fed or fasted state. Fasting lipid levels referto levels of the lipids in the plasma of a subject after a fastingperiod, which is a period of about 8 to 12 hours without food.

In some embodiments, the baseline fasting triglyceride level in thesubject prior to administration of a composition of the presentinvention is greater than 150 mg/dL. In some embodiments, the baselinefasting triglyceride level is 150 mg/dL to 199 mg/dl, alternatively200-499 mg/dL, alternatively over 500 mg/dL.

In some embodiments, the methods of the present invention relate toreducing or decreasing plasma lipid parameters in a subject in needthereof. Lipid parameters include triglycerides, low-density lipoprotein(LDL) cholesterol, total cholesterol, free fatty acids, andnon-high-lipoprotein cholesterol (non-HDL) cholesterol. The lipidparameters may be measured in a fasting state or a fed state. In someembodiments, the methods comprise administration of EPA and/or DPA inthe free fatty acid form or a salt, ester, or derivative form. In someembodiments, the methods comprise a reduction in triglyceride levels ofat least 10%, alternatively at least 15%, alternatively at least 20%,alternatively at least 25%, alternatively at least 30%, alternatively atleast 35%, alternatively at least 40%, alternatively at least 45%, andalternatively at least 50% compared to baseline. In some embodiments,the methods comprise a reduction in total cholesterol levels of at least1%, alternatively at least 2%, alternatively at least 3%, alternativelyat least 4%, alternatively at least 5%, alternatively at least 6%,alternatively at least 7%, alternatively at least 8%, alternatively atleast 9%, alternatively at least 10% compared to baseline. In someembodiments, the methods comprise a reduction in low-density lipoprotein(LDL) levels of at least 10%, alternatively at least 15%, alternativelyat least 20%, alternatively at least 25%, alternatively at least 30%,alternatively at least 35%, alternatively at least 40%, alternatively atleast 45%, and alternatively at least 50% compared to baseline. In someembodiments, the methods comprise a reduction in free fatty acid levelsof at least 5%, alternatively at least 7%, alternatively at least 10%,alternatively at least 15%, alternatively at least 20% compared tobaseline. In some embodiments, the methods comprise a reduction innon-HDL cholesterol levels of at least 1%, alternatively at least 2%,alternatively at least 3%, alternatively at least 4%, alternatively atleast 5%, alternatively at least 6%, alternatively at least 7%,alternatively at least 8%, alternatively at least 9%, alternatively atleast 10%, alternatively at least 20%, alternatively at least 25%,alternatively at least 30% compared to baseline. In some embodiments,the methods comprise an increase in high density lipoprotein (HDL)cholesterol levels of at least 1%, alternatively at least 2%,alternatively at least 3%, alternatively at least 4%, alternatively atleast 5%, alternatively at least 6%, alternatively at least 7%,alternatively at least 8%, alternatively at least 9%, alternatively atleast 10% compared to baseline. In some embodiments, this change inlipid parameters can be achieved after a period of daily administration,such as one week, alternatively one month, alternatively two months,alternatively three months or more.

The present invention provides methods of treatment forhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199 mg/dL),mixed dyslipidemia, or any other diseases or medical conditions asspecified above, by dosing to a subject in need thereof omega-3docosapentaenoic acid (DPA-n3) or its glycerol or ethyl esters. Suchmethod of treatment provide a dose of at least 60 mg DPA-N3 per day,alternatively at least 80 mg DPA-N3 per day, alternatively at least 90mg DPA-N3 per day, alternatively at least 120 mg DPA-N3 per day,alternatively at least 150 mg DPA-N3 per day, alternatively at least 160mg DPA-N3 per day, alternatively at least 180 mg DPA-N3 per day,alternatively at least 200 mg DPA-N3 per day, alternatively at least 250mg DPA-N3 per day, alternatively at least 300 mg DPA-N3 per day,alternatively at least 350 mg DPA-N3 per day, alternatively at least 400mg DPA-N3 per day, alternatively at least 500 mg DPA-N3 per day,alternatively at least 600 mg DPA-N3 per day, alternatively at least 800mg DPA-N3 or its glycerol or ethyl esters per day.

In some embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 docosapentaenoic acid(DPA-n3) or its glycerol or ethyl esters, may be used for the treatmentof hypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a dose of at least 20 mg DPA-N3 per day, alternatively at least25 mg DPA-N3 per day, alternatively at least 30 mg DPA-N3 per day,alternatively at least 40 mg DPA-N3 per day, alternatively at least 50mg DPA-N3 per day, alternatively at least 60 mg DPA-N3 per day,alternatively at least 70 mg DPA-N3 per day, alternatively at least 80mg DPA-N3 per day, alternatively at least 90 mg DPA-N3 per day,alternatively at least 100 mg DPA-N3 per day, alternatively at least 120mg DPA-N3 per day, alternatively at least 150 mg DPA-N3 per day,alternatively at least 160 mg DPA-N3 per day, alternatively at least 180mg DPA-N3 per day, alternatively at least 200 mg DPA-N3 per day,alternatively at least 250 mg DPA-N3 per day, alternatively at least 300mg DPA-N3 per day, alternatively at least 350 mg DPA-N3 per day,alternatively at least 400 mg DPA-N3 per day, alternatively at least 500mg DPA-N3 per day, alternatively at least 600 mg DPA-N3 per day,alternatively alternativelyat least 800 mg DPA-N3 or its glycerol orethyl esters per day.

In other embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 docosapentaenoic acid(DPA-n3) or its glycerol or ethyl esters and which comprise relativelysmall amounts of omega-3 docosahexaenoic acid (DHA-n3), may be used forthe treatment of hypertriglyceridemia (either TG≧500 mg/dL, TG≧200mg/dL, TG≧150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL,or TG150-199 mg/dL), mixed dyslipidemia, or any other diseases ormedical conditions specified above. Such method of treatment provides toa subject in need thereof a dose of at least 20 mg DPA-N3 per day,alternatively at least 25 mg DPA-N3 per day, alternatively at least 30mg DPA-N3 per day, alternatively at least 40 mg DPA-N3 per day,alternatively at least 50 mg DPA-N3 per day, alternatively at least 60mg DPA-N3 per day, alternatively at least 80 mg DPA-N3 per day,alternatively at least 90 mg DPA-N3 per day, alternatively at least 120mg DPA-N3 per day, alternatively at least 150 mg DPA-N3 per day,alternatively at least 160 mg DPA-N3 per day, alternatively at least 180mg DPA-N3 per day, alternatively at least 200 mg DPA-N3 per day,alternatively at least 250 mg DPA-N3 per day, alternatively at least 300mg DPA-N3 per day, alternatively at least 350 mg DPA-N3 per day,alternatively at least 400 mg DPA-N3 per day, alternatively at least 500mg DPA-N3 per day, alternatively at least 600 mg DPA-N3 per day,alternatively alternativelyat least 800 mg DPA-N3 or its glycerol orethyl esters per day, while providing less than 1500 mg of DHA,alternatively less than 1200 mg of DHA, alternatively less than 1000 mgof DHA, alternatively less than 800 mg of DHA, alternatively less than700 mg of DHA, alternatively less than 600 mg of DHA, alternatively lessthan 500 mg of DHA, alternatively less than 400 mg of DHA, alternativelyless than 350 mg of DHA, alternatively less than 300 mg of DHA,alternatively less than 250 mg of DHA, alternatively less than 200 mg ofDHA alternatively less than 150 mg of DHA, alternatively less than 120mg of DHA, alternatively less than 100 mg of DHA, alternatively lessthan 80 mg of DHA, alternatively less than 60 mg of DHA, alternativelyless than 40 mg of DHA, alternatively less than 30 mg of DHA,alternatively less than 25 mg of DHA, alternatively less than 20 mg ofDHA or its glycerol or ethyl esters per day.

In further embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 docosapentaenoic acid(DPA-n3) or its glycerol or ethyl esters and which comprise relativelysmall amounts of omega-3 docosahexaenoic acid (DHA-n3), may be used forthe treatment of hypertriglyceridemia (either TG≧500 mg/dL, TG≧200mg/dL, TG≧150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL,or TG150-199 mg/dL), mixed dyslipidemia, or any other diseases ormedical conditions specified above. Such method of treatment provides toa subject in need thereof a dose of at least 30 mg DPA-N3 per day,alternatively at least 40 mg DPA-N3 per day, alternatively at least 50mg DPA-N3 per day, alternatively at least 60 mg DPA-N3 per day,alternatively at least 80 mg DPA-N3 per day, alternatively at least 90mg DPA-N3 per day, alternatively at least 120 mg DPA-N3 per day,alternatively at least 150 mg DPA-N3 per day, alternatively at least 160mg DPA-N3 per day, alternatively at least 180 mg DPA-N3 per day,alternatively at least 200 mg DPA-N3 per day, alternatively at least 250mg DPA-N3 per day, alternatively at least 300 mg DPA-N3 per day,alternatively at least 350 mg DPA-N3 per day, alternatively at least 400mg DPA-N3 per day, alternatively at least 500 mg DPA-N3 per day,alternatively at least 600 mg DPA-N3 per day, alternatively at least 800mg DPA-N3 per day, alternatively at least 1000 mg DPA-N3 per day,alternatively at least 1200 mg DPA-N3 per day, alternatively at least1500 mg DPA-N3 or its glycerol or ethyl esters per day, while providinga relatively small amount of DHA-N3 such that the DHA:DPA dose ratio isno more than 15:1 of DHA:DPA, alternatively no more than 12:1 ofDHA:DPA, alternatively no more than 10:1 of DHA:DPA, alternatively nomore than 8:1 of DHA:DPA, alternatively no more than 5:1 of DHA:DPA,alternatively no more than 3:1 of DHA:DPA, alternatively no more than2:1 of DHA:DPA, alternatively no more than 1:1 of DHA:DPA, alternativelyno more than 1:2 of DHA:DPA, alternatively no more than 1:3 of DHA:DPA,alternatively no more than 1:5 of DHA:DPA, alternatively no more than1:8 of DHA:DPA, alternatively no more than 1:10 of DHA:DPA,alternatively no more than 1:15 of DHA:DPA, alternatively a relativedaily dose of no more than 1:20 of DHA:DPA.

The present invention provides methods of reducing triglycerides andtreating hypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsas specified above, by dosing to a subject in need thereof omega-3docosapentaenoic acid (HPA-n3) or its glycerol or ethyl esters. Suchmethod of treatment provides a dose of at least 10 mg HPA-N3 per day,alternatively at least 15 mg HPA-N3 per day, alternatively at least 20mg HPA-N3 per day, alternatively at least 25 mg HPA-N3 per day,alternatively at least 30 mg HPA-N3 per day, alternatively at least 40mg HPA-N3 per day, alternatively at least 50 mg HPA-N3 per day,alternatively at least 60 mg HPA-N3 per day, alternatively at least 70mg HPA-N3 per day, alternatively at least 80 mg HPA-N3 per day,alternatively at least 90 mg HPA-N3 per day, alternatively at least 100mg HPA-N3 per day, alternatively at least 120 mg HPA-N3 per day,alternatively at least 150 mg HPA-N3 per day, alternatively at least 160mg HPA-N3 per day, alternatively at least 180 mg HPA-N3 per day,alternatively at least 200 mg HPA-N3 per day, alternatively at least 250mg HPA-N3 per day, alternatively at least 300 mg HPA-N3 per day,alternatively at least 350 mg HPA-N3 per day, alternatively at least 400mg HPA-N3 per day, alternatively at least 500 mg HPA-N3 per day,alternatively at least 600 mg HPA-N3 per day, alternatively at least 800mg HPA-N3 or its glycerol or ethyl esters per day.

In some embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 heneicosapentaenoic acid(HPA-n3) or its glycerol or ethyl esters, may be used for the treatmentof hypertriglyceridemia (either TG-500 mg/dL, TG≧200 mg/dL, TG≧150mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a dose of at least 10 mg HPA-N3 per day, alternatively at least15 mg HPA-N3 per day, alternatively at least 20 mg HPA-N3 per day,alternatively at least 25 mg HPA-N3 per day, alternatively at least 30mg HPA-N3 per day, alternatively at least 40 mg HPA-N3 per day,alternatively at least 50 mg HPA-N3 per day, alternatively at least 60mg HPA-N3 per day, alternatively at least 70 mg HPA-N3 per day,alternatively at least 80 mg HPA-N3 per day, alternatively at least 90mg HPA-N3 per day, alternatively at least 100 mg HPA-N3 per day,alternatively at least 120 mg HPA-N3 per day, alternatively at least 150mg HPA-N3 per day, alternatively at least 160 mg HPA-N3 per day,alternatively at least 180 mg HPA-N3 per day, alternatively at least 200mg HPA-N3 per day, alternatively at least 250 mg HPA-N3 per day,alternatively at least 300 mg HPA-N3 per day, alternatively at least 350mg HPA-N3 per day, alternatively at least 400 mg HPA-N3 per day,alternatively at least 500 mg HPA-N3 per day, alternatively at least 600mg HPA-N3 per day, alternatively alternativelyat least 800 mg HPA-N3 orits glycerol or ethyl esters per day.

In other embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 docosapentaenoic acid(HPA-n3) or its glycerol or ethyl esters and which comprise relativelysmall amounts of omega-3 docosahexaenoic acid (DHA-n3), may be used forthe treatment of hypertriglyceridemia (either TG≧500 mg/dL, TG≧200mg/dL, TG≧150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL,or TG150-199 mg/dL), mixed dyslipidemia, or any other diseases ormedical conditions specified above. Such method of treatment provides toa subject in need thereof a dose of at least 20 mg HPA-N3 per day,alternatively at least 25 mg HPA-N3 per day, alternatively at least 30mg HPA-N3 per day, alternatively at least 40 mg HPA-N3 per day,alternatively at least 50 mg HPA-N3 per day, alternatively at least 60mg HPA-N3 per day, alternatively at least 70 mg HPA-N3 per day,alternatively at least 80 mg HPA-N3 per day, alternatively at least 90mg HPA-N3 per day, alternatively at least 100 mg HPA-N3 per day,alternatively at least 120 mg HPA-N3 per day, alternatively at least 150mg HPA-N3 per day, alternatively at least 160 mg HPA-N3 per day,alternatively at least 180 mg HPA-N3 per day, alternatively at least 200mg HPA-N3 per day, alternatively at least 250 mg HPA-N3 per day,alternatively at least 300 mg HPA-N3 per day, alternatively at least 350mg HPA-N3 per day, alternatively at least 400 mg HPA-N3 per day,alternatively at least 500 mg HPA-N3 per day, alternatively at least 600mg HPA-N3 per day, alternatively alternativelyat least 800 mg HPA-N3 orits glycerol or ethyl esters per day, while providing less than 1500 mgof DHA, alternatively less than 1200 mg of DHA, alternatively less than1000 mg of DHA, alternatively less than 800 mg of DHA, alternativelyless than 700 mg of DHA, alternatively less than 600 mg of DHA,alternatively less than 500 mg of DHA, alternatively less than 400 mg ofDHA, alternatively less than 350 mg of DHA, alternatively less than 300mg of DHA, alternatively less than 250 mg of DHA, alternatively lessthan 200 mg of DHA or its glycerol or ethyl esters per day,alternatively less than 150 mg of DHA, alternatively less than 120 mg ofDHA, alternatively less than 100 mg of DHA, alternatively less than 80mg of DHA, alternatively less than 60 mg of DHA, alternatively less than40 mg of DHA, alternatively less than 30 mg of DHA, alternatively lessthan 25 mg of DHA, alternatively less than 20 mg of DHA or its glycerolor ethyl esters per day.

In further embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3 heneicosapentaenoic acid(HPA-n3) or its glycerol or ethyl esters and which comprise relativelysmall amounts of omega-3 docosahexaenoic acid (DHA-n3), may be used forthe treatment of hypertriglyceridemia (either TG≧500 mg/dL, TG≧200mg/dL, TG≧150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL,or TG150-199 mg/dL), mixed dyslipidemia, or any other diseases ormedical conditions specified above. Such method of treatment provides toa subject in need thereof a dose of at least 10 mg HPA-N3 per day,alternatively at least 15 mg HPA-N3 per day, alternatively at least 20mg HPA-N3 per day, alternatively at least 25 mg HPA-N3 per day,alternatively at least 30 mg HPA-N3 per day, alternatively at least 40mg HPA-N3 per day, alternatively at least 50 mg HPA-N3 per day,alternatively at least 60 mg HPA-N3 per day, alternatively at least 70mg HPA-N3 per day, alternatively at least 80 mg HPA-N3 per day,alternatively at least 90 mg HPA-N3 per day, alternatively at least 100mg HPA-N3 per day, alternatively at least 120 mg HPA-N3 per day,alternatively at least 150 mg HPA-N3 per day, alternatively at least 160mg HPA-N3 per day, alternatively at least 180 mg HPA-N3 per day,alternatively at least 200 mg HPA-N3 per day, alternatively at least 250mg HPA-N3 per day, alternatively at least 300 mg HPA-N3 per day,alternatively at least 350 mg HPA-N3 per day, alternatively at least 400mg HPA-N3 per day, alternatively at least 500 mg HPA-N3 per day,alternatively at least 600 mg HPA-N3 per day, alternatively at least 800mg HPA-N3 per day, alternatively at least 1000 mg HPA-N3 per day,alternatively at least 1200 mg HPA-N3 per day, alternatively at least1500 mg HPA-N3 or its glycerol or ethyl esters per day, while providinga relatively small amount of DHA-N3 such that the DHA:HPA dose ratio isno more than 15:1 of DHA:HPA, alternatively no more than 12:1 ofDHA:HPA, alternatively no more than 10:1 of DHA:HPA, alternatively nomore than 8:1 of DHA:HPA, alternatively no more than 5:1 of DHA:HPA,alternatively no more than 3:1 of DHA:HPA, alternatively no more than2:1 of DHA:HPA, alternatively no more than 1:1 of DHA:HPA, alternativelyno more than 1:2 of DHA:HPA, alternatively no more than 1:3 of DHA:HPA,alternatively no more than 1:5 of DHA:HPA, alternatively no more than1:8 of DHA:HPA, alternatively no more than 1:10 of DHA:HPA,alternatively no more than 1:15 of DHA:HPA, alternatively a relativedaily dose of no more than 1:20 of DHA:HPA.

The present invention, incorporates methods of treatment forhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199 mg/dL),mixed dyslipidemia, or any other diseases or medical conditions asspecified above, by dosing to a subject in need thereofomega-3-pentaenoic acids or their glycerol or ethyl esters. Thesemethods provide to a subject in need thereof significant amounts ofomega-3-pentaenoic acids or their glycerol or ethyl esters and whileproviding only small amounts of omega-3 docosahexaenoic acid (DHA-n3).Such methods of treatment provides to a subject in need thereof a doseof at least 100 mg omega-3-pentaenoic acids per day, alternatively atleast 200 mg omega-3-pentaenoic acids per day, alternatively at least300 mg omega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6100 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing less than 1900 mg of DHA, alternatively less than 1500mg of DHA, alternatively less than 1200 mg of DHA, alternatively lessthan 1000 mg of DHA, alternatively less than 800 mg of DHA,alternatively less than 700 mg of DHA, alternatively less than 600 mg ofDHA, alternatively less than 500 mg of DHA, alternatively less than 400mg of DHA, alternatively less than 350 mg of DHA, alternatively lessthan 300 mg of DHA, alternatively less than 250 mg of DHA, alternativelyless than 200 mg of DHA, alternatively less than 150 mg of DHA,alternatively less than 120 mg of DHA, alternatively less than 100 mg ofDHA, alternatively less than 80 mg of DHA, alternatively less than 60 mgof DHA, alternatively less than 40 mg of DHA, alternatively less than 30mg of DHA, alternatively less than 25 mg of DHA, alternatively less than20 mg of DHA or its glycerol or ethyl esters per day.

In other embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3-pentaenoic acids or theirglycerol or ethyl esters and which comprise relatively small amounts ofomega-3 docosahexaenoic acid (DHA-n3), may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199 mg/dL),mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a dose of at least 100 mg omega-3-pentaenoic acids per day,alternatively at least 200 mg omega-3-pentaenoic acids per day,alternatively at least 300 mg omega-3-pentaenoic acids per day,alternatively at least 500 mg omega-3-pentaenoic acids per day,alternatively at least 700 mg omega-3-pentaenoic acids per day,alternatively at least 900 mg omega-3-pentaenoic acids per day,alternatively at least 1000 mg omega-3-pentaenoic acids per day,alternatively at least 1500 mg omega-3-pentaenoic acids per day,alternatively at least 1900 mg omega-3-pentaenoic acids per day,alternatively at least 2000 mg omega-3-pentaenoic acids per day,alternatively at least 2500 mg omega-3-pentaenoic acids per day,alternatively at least 2900 mg omega-3-pentaenoic acids per day,alternatively at least 3000 mg omega-3-pentaenoic acids per day,alternatively at least 3500 mg omega-3-pentaenoic acids per day,alternatively at least 3900 mg omega-3-pentaenoic acids per day,alternatively at least 4000 mg omega-3-pentaenoic acids per day or theirglycerol or ethyl esters, while providing a relatively small amount ofDHA-N3 such that the DHA:DPA ratio is no more than 15:1 of DHA:DPA,alternatively no more than 12:1 of DHA:DPA, alternatively no more than10:1 of DHA:DPA, alternatively no more than 8:1 of DHA:DPA,alternatively no more than 5:1 of DHA:DPA, alternatively no more than3:1 of DHA:DPA, alternatively no more than 2:1 of DHA:DPA, alternativelyno more than 1:1 of DHA:DPA, alternatively no more than 1:2 of DHA:DPA,alternatively no more than 1:3 of DHA:DPA, alternatively no more than1:5 of DHA:DPA, alternatively no more than 1:8 of DHA:DPA, alternativelyno more than 1:10 of DHA:DPA, alternatively no more than 1:15 ofDHA:DPA, alternatively a relative amount of no more than 1:20 ofDHA:DPA.

In other embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3-pentaenoic acids or theirglycerol or ethyl esters and which comprise relatively small amounts ofomega-3 docosahexaenoic acid (DHA-n3), may be used for the reduction oftriglycerides and treatment of hypertriglyceridemia (either TG500 mg/dL,TG≧200 mg/dL, TG150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499mg/dL, or TG150-199 mg/dL), mixed dyslipidemia, or any other diseases ormedical conditions specified above. Such method of treatment provides toa subject in need thereof a dose of at least 100 mg omega-3-pentaenoicacids per day, alternatively at least 200 mg omega-3-pentaenoic acidsper day, alternatively at least 300 mg omega-3-pentaenoic acids per day,alternatively at least 500 mg omega-3-pentaenoic acids per day,alternatively at least 700 mg omega-3-pentaenoic acids per day,alternatively at least 900 mg omega-3-pentaenoic acids per day,alternatively at least 1000 mg omega-3-pentaenoic acids per day,alternatively at least 1500 mg omega-3-pentaenoic acids per day,alternatively at least 1900 mg omega-3-pentaenoic acids per day,alternatively at least 2000 mg omega-3-pentaenoic acids per day,alternatively at least 2500 mg omega-3-pentaenoic acids per day,alternatively at least 2900 mg omega-3-pentaenoic acids per day,alternatively at least 3000 mg omega-3-pentaenoic acids per day,alternatively at least 3500 mg omega-3-pentaenoic acids per day,alternatively at least 3900 mg omega-3-pentaenoic acids per day,alternatively at least 4000 mg omega-3-pentaenoic acids per day or theirglycerol or ethyl esters, while providing a relatively small amount ofDHA-N3 such that the DHA:HPA ratio is no more than 15:1 of DHA:HPA,alternatively no more than 12:1 of DHA:HPA, alternatively no more than10:1 of DHA:HPA, alternatively no more than 8:1 of DHA:HPA,alternatively no more than 5:1 of DHA:HPA, alternatively no more than3:1 of DHA:HPA, alternatively no more than 2:1 of DHA:HPA, alternativelyno more than 1:1 of DHA:HPA, alternatively no more than 1:2 of DHA:HPA,alternatively no more than 1:3 of DHA:HPA, alternatively no more than1:5 of DHA:HPA, alternatively no more than 1:8 of DHA:HPA, alternativelyno more than 1:10 of DHA:HPA, alternatively no more than 1:15 ofDHA:HPA, alternatively a relative amount of no more than 1:20 ofDHA:HPA.

In further embodiments, the compositions of the present invention, whichmay comprise significant amounts of omega-3-pentaenoic acids or theirglycerol or ethyl esters and which comprise relatively small amounts ofomega-3 docosahexaenoic acid (DHA-n3), may be used for the reduction oftriglycerides and treatment of hypertriglyceridemia (either TG≧500mg/dL, TG≧200 mg/dL, TG≧150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL,TG350-499 mg/dL, or TG150-199 mg/dL), mixed dyslipidemia, or any otherdiseases or medical conditions specified above. Such method of treatmentprovides to a subject in need thereof a dose of at least 100 mgomega-3-pentaenoic acids per day, alternatively at least 200 mgomega-3-pentaenoic acids per day, alternatively at least 300 mgomega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6000 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing a relatively small amount of DHA-N3 as compared to theamount of omega-3-pentaenoic acids (N-3-5enoicFA) such that theDHA:N3-5enoicFA ratio is no more than 15:1 of DHA:N3-5enoicFA,alternatively no more than 12:1 of DHA:N3-5enoicFA, alternatively nomore than 10:1 of DHA:N3-5enoicFA, alternatively no more than 8:1 ofDHA:N3-5enoicFA, alternatively no more than 5:1 of DHA:N3-5enoicFA,alternatively no more than 3:1 of DHA:N3-5enoicFA, alternatively no morethan 2:1 of DHA:N3-5enoicFA, alternatively no more than 1:1 ofDHA:N3-5enoicFA, alternatively no more than 1:2 of DHA:N3-5enoicFA,alternatively no more than 1:3 of DHA:N3-5enoicFA, alternatively no morethan 1:5 of DHA:N3-5enoicFA, alternatively no more than 1:8 ofDHA:N3-5enoicFA, alternatively no more than 1:10 of DHA:N3-5enoicFA,alternatively no more than 1:15 of DHA:N3-5enoicFA, alternatively arelative amount of no more than 1:20 of DHA:N3-5enoicFA.

In some embodiments, the improved profile of the compositions of thepresent invention may be demonstrated upon treatment of a subject bydifferentially altering the ration between blood platelets and fragmentsthereof (also known as platelet microparticles). Such fragments may beevaluated as a whole or examined and described as fragmentsub-categories.

In other embodiments, the improved profile of the compositions of thepresent invention may be demonstrated upon treatment of a subject bydifferentially altering the surface charge of blood platelets andfragments thereof, either in resting state (non-activated platelets) oractivated stage.

In yet other embodiments, treatment of a subject or patient withcompositions of the present invention affect the coagulatory cascade anddifferentially alter coagulation or bleeding times or plateletaggregation times and density.

In further embodiments, treatment with compositions of the presentinvention improves the vascular healing process in response toatherogenic disease. Such healing may be demonstrated by reducedstenosis and/or restenosis over time, reduced or lesser increase inintima-media thickness (IMT) of the arterial wall, larger lumen sizeand/or larger vascular diameter at vascular sites with stenosis or clotbuilt-up, as determined by either by intravascular ultrasound (IVUS),radiographic, radiologic, non-invasive ultrasound, tomography, magneticresonance interference (MRI), or other acceptable methods. In otherembodiments, such improved healing may be demonstrated by the vascularwall composition, such as a reduced foam cell presence or fibrillatedtissue in the vessel wall. In yet other embodiments, such improvedvascular healing is demonstrated by improved inflammatory markers in thevascular wall.

The improved profile resulting from treatment with the compositions ofthe present invention may also be demonstrated by a differentiatedimpact on blood/serum/plasma lipid and lipoprotein levels in a mammal;these include, but are not limited to: Triglycerides (TG),total-cholesterol, non-HDL-cholesterol, LDL-cholesterol,VLDL-cholesterol, apolipoprotein B, apolipoprotein A, apolipoproteinC-III, HDL-cholesterol, and Lp-PLA2. The compositions of the presentinvention may also be used to provide a beneficial impact on the one ormore of the following: apolipoprotein A-I (apo A-I), apolipoprotein B(apo B), apo A-I/apo B ratio, lipoprotein(a) (Lp[a]),lipoprotein-associated phospholipase A2 (Lp-PLA2), low densitylipoprotein (LDL) particle number and size, oxidized LDL, C-reactiveprotein (CRP), high sensitivity C-reactive protein (HSCRP),intracellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin,vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation106 (CD106), interleleukin-1β (IL-1β), interleukin-2 (IL-2),interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10),interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18),tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β),plasminogen activator inhibitor-1 (PAI-1), homocysteine, thromboxane B2(TXB2), thromboxane A2 (TXA2), 2,3-dinor thromboxane B2, free fattyacids (FFA), serum amyloid A1, serum amyloid A2, serum amyloid A3, serumamyloid A4, thiobarbituric acid (TBA) reacting material, adiponectin(GBP-28), hemoglobin A1c (HbA1c), macrophage colony stimulating factor(M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF),fibrinogen, fibrin D-dimer, platelet derived-microparticles, meanplatelet volume (MPV), platelet subpopulations, heart rate, systolic anddiastolic blood pressure, nuclear factor kappa-light-chain enhancer ofactivated B cells (NF-κβ), adenosine diphosphate induced plateletaggregation, platelet endothelial cell adhesion molecule (PECAM-1),vitronectin receptor (α_(v)β_(v)), and glycoprotein IIb/IIIa(gpIIIb/IIIa). The compositions of the present invention may also beused in methods of treating, preventing, and reducing symptomsassociated with conditions associated with the above.

Methods to determine comparative blood/serum/plasma lipid andlipoprotein levels and therapeutic effects on these levels in mammalsare generally know to those skilled in the art and are typically basedon fasting lipid and lipoprotein levels. Differences of active treatmentversus placebo are generally assessed on a group of subjects versusanother group of subjects basis, with significant changes noted if thep-value for the appropriate statistical comparison is equal to or lessthan 0.05. P-values larger than 0.05 but equal to or less than 0.10 maybe considered borderline significant (BS). P-values larger than 0.10 aregenerally considered not significant (NS). In one embodiment, treatmentwith the compositions of the present invention is more potent than otheromega-3 compositions known in the prior art (such as LOVAZA®, EPANOVA™or AMR101) in reducing as compared to placebo or baseline: TG levels,Total-cholesterol levels, non-HDL-cholesterol levels, VLDL-cholesterollevels, LDL-cholesterol levels, apolipoprotein B levels, apolipoproteinC-III levels, Lp-PLA2 levels, or any combinations thereof. In otherembodiments, such more potent effects in reducing these parameters areachieved in patients with baseline TG over 500 mg/dL, in patients onstatin treatment with baseline TG in the 200-499 mg/dL range, inpatients not on statin treatment with baseline LDL-cholesterol of 190mg/dL or higher and with TG in the 300-700 mg/dL range, in patients noton statin treatment with baseline LDL-cholesterol of 190 mg/dL or higherand with TG in the 350-700 mg/dL range, in patients not on statintreatment with baseline LDL-cholesterol of 190 mg/dL or higher and withTG in the 300-750 mg/dL range, in patients not on statin treatment withbaseline LDL-cholesterol of 190 mg/dL or higher and with TG in the350-750 mg/dL range, or in patients not on statin treatment withbaseline non-HDL-cholesterol of 200 mg/dL or higher and with TG in the300-700 mg/dL range, or in patients not on statin treatment withbaseline non-HDL-cholesterol of 200 mg/dL or higher and with TG in the350-700 mg/dL range, or in patients not on statin treatment withbaseline non-HDL-cholesterol of 200 mg/dL or higher and with TG in the300-750 mg/dL range, or in patients not on statin treatment withbaseline non-HDL-cholesterol of 200 mg/dL or higher and with TG in the350-750 mg/dL range.

In a further embodiment, treatment with the compositions of the presentinvention together with statin therapy is more potent than other omega-3compositions known in the prior art (such as LOVAZA®, EPANOVA™ orAMR101) in reducing as compared to placebo or baseline: TG levels,Total-cholesterol levels, non-HDL-cholesterol levels, VLDL-cholesterollevels, LDL-cholesterol levelsapolipoprotein B levels, apolipoproteinC-III levels, Lp-PLA2 levels, or any combinations thereof. In otherembodiments, such more potent effects in reducing these parameters areachieved in patients with baseline TG over 500 mg/dL, in patients onstatin treatment with baseline TG in the 200-499 mg/dL range, inpatients not on baseline statin treatment with baseline LDL-cholesterolof 190 mg/dL or higher and with TG in the 300-700 mg/dL range, inpatients not on baseline statin treatment with baseline LDL-cholesterolof 190 mg/dL or higher and with TG in the 350-700 mg/dL range, inpatients not on baseline statin treatment with baseline LDL-cholesterolof 190 mg/dL or higher and with TG in the 300-750 mg/dL range, inpatients not on baseline statin treatment with baseline LDL-cholesterolof 190 mg/dL or higher and with TG in the 350-750 mg/dL range, or inpatients not on baseline statin treatment with baselinenon-HDL-cholesterol of 200 mg/dL or higher and with TG in the 300-700mg/dL range, or in patients not on baseline statin treatment withbaseline non-HDL-cholesterol of 200 mg/dL or higher and with TG in the350-700 mg/dL range, or in patients not on baseline statin treatmentwith baseline non-HDL-cholesterol of 200 mg/dL or higher and with TG inthe 300-750 mg/dL range, or in patients not on baseline statin treatmentwith baseline Non-HDL-cholesterol of 200 mg/dL or higher and with TG inthe 350-750 mg/dL range.

The present invention also provides methods of reducing triglycerideslevels in a subject, wherein the non-HDL cholesterol levels, such asLDL-cholesterol levels, of the subject are reduced or not significantlyincreased from, for example, baseline levels before treatment. In someembodiments, treatment with the compositions of the present inventionresults in a minor (less than 10% change from baseline, alternativelyless than 5%) and/or non-significant change in non-HDL cholesterollevels (such as LDL-cholesterol levels) as compared to placebo inpatients with baseline TG levels above 500 mg/dL. In a furtherembodiment, treatment with the compositions of the present inventionresults in reductions of LDL-cholesterol levels as compared to placeboin patients with baseline TG levels above 500 mg/dL. In someembodiments, the methods involve coadministration of a statin.

In another embodiment, treatment with the compositions of the presentinvention as compared to placebo does not increase LDL-cholesterollevels in patients with baseline TG levels of 200-499 mg/dL while onstatin therapy.

In yet another embodiment, treatment with the compositions of thepresent invention as compared to placebo results in significantreductions in LDL-cholesterol levels in patients with baseline TG levelsof 200-499 mg/dL while on statin therapy.

In a further embodiment, the compositions of the present invention ascompared to placebo result in significant reductions in LDL-cholesterollevels in patients not on statin treatment with LDL-cholesterol of 190mg/dL or higher and with TG in the 300-700 mg/dL range, in patients noton statin treatment with LDL-cholesterol of 190 mg/dL or higher and withTG in the 350-700 mg/dL range, in patients not on statin treatment withLDL-cholesterol of 190 mg/dL or higher and with TG in the 300-750 mg/dLrange, or in patients not on statin treatment with LDL-cholesterol of190 mg/dL or higher and with TG in the 350-750 mg/dL range. Finally,another embodiment, the compositions of the present invention ascompared to placebo result in significant reductions in LDL-cholesterollevels in patients not on statin treatment with non-HDL-cholesterol of200 mg/dL or higher and with TG in the 300-700 mg/dL range, in patientsnot on statin treatment with Non-HDL-cholesterol of 200 mg/dL or higherand with TG in the 350-700 mg/dL range, in patients not on statintreatment with non-HDL-cholesterol of 200 mg/dL or higher and with TG inthe 300-750 mg/dL range, or in patients not on statin treatment withNon-HDL-cholesterol of 200 mg/dL or higher and with TG in the 350-750mg/dL range.

In another embodiment, treatment with the compositions of the presentinvention together with statin therapy results in significant reductionsin LDL-cholesterol levels as compared to placebo in patients not onstatin treatment at baseline with baseline LDL-cholesterol of 190 mg/dLor higher and with TG in the 300-700 mg/dL range, in patients not onbaseline statin treatment with baseline LDL-cholesterol of 190 mg/dL orhigher and with TG in the 350-700 mg/dL range, in patients not onbaseline statin treatment with baseline LDL-cholesterol of 190 mg/dL orhigher and with TG in the 300-750 mg/dL range, or in patients not onbaseline statin treatment with baseline LDL-cholesterol of 190 mg/dL orhigher and with TG in the 350-750 mg/dL range.

Finally, another embodiment, treatment with the compositions of thepresent invention together with statin therapy results in significantreductions in LDL-cholesterol levels as compared to placebo in patientsnot on baseline statin treatment with baseline non-HDL-cholesterol of200 mg/dL or higher and with TG in the 300-700 mg/dL range, in patientsnot on baseline statin treatment with baseline non-HDL-cholesterol of200 mg/dL or higher and with TG in the 350-700 mg/dL range, in patientsnot on baseline statin treatment with baseline non-HDL-cholesterol of200 mg/dL or higher and with TG in the 300-750 mg/dL range, or inpatients not on baseline statin treatment with baselineNon-HDL-cholesterol of 200 mg/dL or higher and with TG in the 350-750mg/dL range.

In another embodiment, the compositions of the present invention aremore potent than other omega-3 compositions known in the prior art (suchas LOVAZA®, EPANOVA™ or AMR101) in increasing as compared to placebo orbaseline HDL-cholesterol levels, apolipoprotein-A levels, or acombination thereof.

In yet another embodiment, the compositions of the present invention aremore potent than other omega-3 compositions known in the prior art (suchas LOVAZA®, EPANOVA™ or AMR101) in decreasing as compared to placebo orbaseline Apolipoprotein-B (Apo-B) levels, Apolipoprotein-CIII levels,Lp-PLA2 levels or any combination thereof.

In further embodiments, the compositions of the present invention ascompared to placebo or baseline are more potent than other omega-3compositions known in the prior art (such as LOVAZA®, EPANOVA™ orAMR101) in reducing TG while causing a lesser increase inLDL-cholesterol, a lesser non-significant increase in LDL-cholesterol,no increase in LDL-cholesterol at all, or a more potent reduction inLDL-cholesterol at in patients with baseline TG levels above 500 mg/dL.

In some embodiments, the use of the compositions of the presentinvention may allow for a reduction in the dose of the statin requiredfor a subject. For example, the coadministration of the composition ofthe present invention in a subject receiving statin therapy may allowfor the reduction of the dose of the statin, compared to subject notbeing co-administered a composition of the present invention. In someembodiments, the dose of the statin may be reduced by at least 10%,alternatively at least 25%, alternatively at least 50%, or alternativelyat least 75%.

In some embodiments, the use of the compositions of the presentinvention may reduce the time needed for a subject to reach therecommended blood levels. For example, the administration ofcompositions of the present invention may allow a subject to reach goallipid levels, for example, those described in the NCEP ATP IIIGuidelines, or any levels recommended by a health care practitioner. Insome embodiments, the reduction of time is greater than 5%,alternatively greater than 15%, alternatively greater than 25%,alternatively greater than 50%, and alternatively greater than 75%.

The compositions of the present invention are also useful to treatcoronary heart disease (CHD), vascular disease, atherosclerotic diseaseor related conditions. The compositions of the present invention mayalso be use for the treatment and/or prevention and/or reduction ofcardiac events and/or cardiovascular events and/or vascular eventsand/or symptoms. Determination of such cardiovasculardiseases/conditions and prevention of events/symptoms in mammals andmethods to determine treatment and preventative/therapeutic effectstherefore are generally know to those skilled in the art.

The present invention also relates to treatment of such conditions inwith concomitant treatments regimes or combination products with otheractive pharmaceutical ingredients. Such concomitant or fixed combinationtreatments may include a statin, an anticoagulant (such as aspirin orclopidogrel), an antihypertensive (such as a diuretic, beta-blocker,calcium channel blocker, ACE-inhibitor, angiotensin II receptor (ARB)antagonist), or other treatments for cardiovascular diseases.

The present invention also includes pharmaceutical compositions, forexample, a unit dosage, comprising one or more HMG-CoA reductaseinhibitors (“statins”) and the omega-3 fatty acid composition of thepresent invention. The present invention may incorporate now known orfuture known statins in an amount generally recognized as safe. Thereare currently seven statins that are widely available: atorvastatin,rosuvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, andsimvastatin. An eight statin, cerivastatin, has been removed from theU.S. market at the time of this writing. However, it is conceivable toone skilled in the art that cerivastatin may be used in conjunction withsome embodiments of the present invention if cerivastatin is ultimatelydetermined to be safe and effective in certain treatment regimens. Suchstatins are typically used at their common daily doses, which include,but are not limited to lovastatin 10 mg, 20 mg, 40 mg; pravastatin 10mg, 20 mg, 40 mg, 80 mg; simvastatin 5 mg, 10 mg, 20 mg, 40 mg, 80 mg;fluvastatin 20 mg, 40 mg, 80 mg; atorvastatin 10 mg, 20 mg, 40 mg, 80mg; rosuvastatin 5 mg, 10 mg, 20 mg, 40 mg; and pitavastatin 1 mg, 2 mg,4 mg, 8 mg.

Generally, the effect of statins is dose dependent, i.e., the higher thedose, the greater the therapeutic affect. However, the effect of eachstatin is different, and therefore the level of therapeutic effect ofone statin cannot be necessarily be directly correlated to the level oftherapeutic effects of other statins. For example, bioavailabilityvaries widely among the statins. Specifically, it has been shown thatsimvastatin is less than 5% bioavailable, while fluvastatin isapproximately 24% bioavailable. Statins are absorbed at rates rangingfrom about 30% with lovastatin to 98% with fluvastatin. First-passmetabolism occurs in all statins except pravastatin. Pravastatin is alsothe least protein-bound of the statins (about 50%), compared with theothers, which are more than 90% protein-bound. Accordingly, the statinspossess distinct properties from one another. The combination productsof this invention involving each statin or a plurality of statins arealso distinct.

The present invention also includes methods of treatment, comprisingdosing of one or more statins and the omega-3 fatty acid composition ofthe present invention, either as concomitant therapy or in a fixed dosecombination product comprising both a statin and the composition of thepresent invention. This method of treatment combines the administrationof one or more statins at its common dose or an alternative dose withthe composition of the present invention.

In some embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3 docosapentaenoic acid (DPA-n3)or its glycerol or ethyl esters, together with a common or alternativestatin dose, may be used for the treatment of hypertriglyceridemia(either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL, TG 200-499 mg/dL,TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199 mg/dL), mixeddyslipidemia, or any other diseases or medical conditions specifiedabove. Such methods of treatment provide to a subject in need thereof adose of at least 30 mg DPA-N3 per day, alternatively at least 40 mgDPA-N3 per day, alternatively at least 50 mg DPA-N3 per day,alternatively at least 60 mg DPA-N3 per day, alternatively at least 70mg DPA-N3 per day, alternatively at least 80 mg DPA-N3 per day,alternatively at least 90 mg DPA-N3 per day, alternatively at least 100mg DPA-N3 per day, alternatively at least 120 mg DPA-N3 per day,alternatively at least 150 mg DPA-N3 per day, alternatively at least 160mg DPA-N3 per day, alternatively at least 180 mg DPA-N3 per day,alternatively at least 200 mg DPA-N3 per day, alternatively at least 250mg DPA-N3 per day, alternatively at least 300 mg DPA-N3 per day,alternatively at least 350 mg DPA-N3 per day, alternatively at least 400mg DPA-N3 per day, alternatively at least 500 mg DPA-N3 per day,alternatively at least 600 mg DPA-N3 per day, alternatively at least 800mg DPA-N3 or its glycerol or ethyl esters per day together with a commonor alternative statin dose. In some embodiments, the compositions of thepresent invention, which comprise significant amounts of omega-3docosapentaenoic acid (HPA-n3) or its glycerol or ethyl esters, togetherwith a common or alternative statin dose, may be used for the treatmentof hypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such methods of treatment provide to a subject in needthereof a dose of at least 10 mg HPA-N3 per day, alternatively at least15 mg HPA-N3 per day, alternatively at least 20 mg HPA-N3 per day,alternatively at least 25 mg HPA-N3 per day, alternatively at least 30mg HPA-N3 per day, alternatively at least 40 mg HPA-N3 per day,alternatively at least 50 mg HPA-N3 per day, alternatively at least 60mg HPA-N3 per day, alternatively at least 80 mg HPA-N3 per day,alternatively at least 90 mg HPA-N3 per day, alternatively at least 120mg HPA-N3 per day, alternatively at least 150 mg HPA-N3 per day,alternatively at least 160 mg HPA-N3 per day, alternatively at least 180mg HPA-N3 per day, alternatively at least 200 mg HPA-N3 per day,alternatively at least 250 mg HPA-N3 per day, alternatively at least 300mg HPA-N3 per day, alternatively at least 350 mg HPA-N3 per day,alternatively at least 400 mg HPA-N3 per day, alternatively at least 500mg HPA-N3 per day, alternatively at least 600 mg HPA-N3 per day,alternatively at least 800 mg HPA-N3 or its glycerol or ethyl esters perday together with a common or alternative statin dose.

In other embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3 docosapentaenoic acid (DPA-n3)or its glycerol or ethyl esters and which comprise relatively smallamounts of omega-3 docosahexaenoic acid (DHA-n3), together with a commonor alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a common or alternative statin dose together with a dose of atleast 30 mg DPA-N3 per day, alternatively at least 40 mg DPA-N3 per day,alternatively at least 50 mg DPA-N3 per day, alternatively at least 60mg DPA-N3 per day, alternatively at least 80 mg DPA-N3 per day,alternatively at least 90 mg DPA-N3 per day, alternatively at least 120mg DPA-N3 per day, alternatively at least 150 mg DPA-N3 per day,alternatively at least 160 mg DPA-N3 per day, alternatively at least 180mg DPA-N3 per day, alternatively at least 200 mg DPA-N3 per day,alternatively at least 250 mg DPA-N3 per day, alternatively at least 300mg DPA-N3 per day, alternatively at least 350 mg DPA-N3 per day,alternatively at least 400 mg DPA-N3 per day, alternatively at least 500mg DPA-N3 per day, alternatively at least 600 mg DPA-N3 per day,alternatively at least 800 mg DPA-N3 or its glycerol or ethyl esters perday, while providing less than 2000 mg of DHA, alternatively less than1900 mg of DHA, alternatively less than 1500 mg of DHA, alternativelyless than 1200 mg of DHA, alternatively less than 1000 mg of DHA,alternatively less than 800 mg of DHA, alternatively less than 700 mg ofDHA, alternatively less than 600 mg of DHA, alternatively less than 500mg of DHA, alternatively less than 400 mg of DHA, alternatively lessthan 350 mg of DHA, alternatively less than 300 mg of DHA, alternativelyless than 250 mg of DHA, alternatively less than 200 mg of DHA,alternatively less than 150 mg of DHA, alternatively less than 120 mg ofDHA, alternatively less than 100 mg of DHA, alternatively less than 80mg of DHA, alternatively less than 60 mg of DHA, alternatively less than50 mg of DHA, alternatively less than 40 mg of DHA, alternatively lessthan 30 mg of DHA, alternatively less than 25 mg of DHA, alternativelyless than 20 mg of DHA or its glycerol or ethyl esters per day.

In other embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3 docosapentaenoic acid (HPA-n3)or its glycerol or ethyl esters and which comprise relatively smallamounts of omega-3 docosahexaenoic acid (DHA-n3), together with a commonor alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG150 mg/dL, TG200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199 mg/dL),mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a common or alternative statin dose together with a dose of atleast 10 mg HPA-N3 per day, alternatively at least 15 mg HPA-N3 per day,alternatively at least 20 mg HPA-N3 per day, alternatively at least 25mg HPA-N3 per day, alternatively at least 30 mg HPA-N3 per day,alternatively at least 40 mg HPA-N3 per day, alternatively at least 50mg HPA-N3 per day, alternatively at least 60 mg HPA-N3 per day,alternatively at least 80 mg HPA-N3 per day, alternatively at least 90mg HPA-N3 per day, alternatively at least 120 mg HPA-N3 per day,alternatively at least 150 mg HPA-N3 per day, alternatively at least 160mg HPA-N3 per day, alternatively at least 180 mg HPA-N3 per day,alternatively at least 200 mg HPA-N3 per day, alternatively at least 250mg HPA-N3 per day, alternatively at least 300 mg HPA-N3 per day,alternatively at least 350 mg HPA-N3 per day, alternatively at least 400mg HPA-N3 per day, alternatively at least 500 mg HPA-N3 per day,alternatively at least 600 mg HPA-N3 per day, alternatively at least 800mg HPA-N3 or its glycerol or ethyl esters per day, while providing lessthan 2000 mg of DHA, alternatively less than 1900 mg of DHA,alternatively less than 1500 mg of DHA, alternatively less than 1200 mgof DHA, alternatively less than 1000 mg of DHA, alternatively less than800 mg of DHA, alternatively less than 700 mg of DHA, alternatively lessthan 600 mg of DHA, alternatively less than 500 mg of DHA, alternativelyless than 400 mg of DHA, alternatively less than 350 mg of DHA,alternatively less than 300 mg of DHA, alternatively less than 250 mg ofDHA, alternatively less than 200 mg of DHA, alternatively less than 150mg of DHA, alternatively less than 120 mg of DHA, alternatively lessthan 100 mg of DHA, alternatively less than 80 mg of DHA, alternativelyless than 60 mg of DHA, alternatively less than 50 mg of DHA,alternatively less than 40 mg of DHA, alternatively less than 30 mg ofDHA, alternatively less than 25 mg of DHA, alternatively less than 20 mgof DHA or its glycerol or ethyl esters per day.

In further embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3 docosapentaenoic acid (DPA-n3)or its glycerol or ethyl esters and which comprise relatively smallamounts of omega-3 docosahexaenoic acid (DHA-n3), together with a commonor alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a common or alternative statin dose together with a dose of atleast 30 mg DPA-N3 per day, alternatively at least 40 mg DPA-N3 per day,alternatively at least 50 mg DPA-N3 per day, alternatively at least 60mg DPA-N3 per day, alternatively at least 70 mg DPA-N3 per day,alternatively at least 80 mg DPA-N3 per day, alternatively at least 90mg DPA-N3 per day, alternatively at least 100 mg DPA-N3 per day,alternatively at least 120 mg DPA-N3 per day, alternatively at least 150mg DPA-N3 per day, alternatively at least 160 mg DPA-N3 per day,alternatively at least 180 mg DPA-N3 per day, alternatively at least 200mg DPA-N3 per day, alternatively at least 250 mg DPA-N3 per day,alternatively at least 300 mg DPA-N3 per day, alternatively at least 350mg DPA-N3 per day, alternatively at least 400 mg DPA-N3 per day,alternatively at least 500 mg DPA-N3 per day, alternatively at least 600mg DPA-N3 per day, alternatively at least 800 mg DPA-N3 per day,alternatively at least 1000 mg DPA-N3 per day, alternatively at least1200 mg DPA-N3 per day, alternatively at least 1500 mg DPA-N3 or itsglycerol or ethyl esters per day, while providing a relatively smallamount of DHA-N3 such that the DHA:DPA dose ratio is no more than 15:1of DHA:DPA, alternatively no more than 12:1 of DHA:DPA, alternatively nomore than 10:1 of DHA:DPA, alternatively no more than 8:1 of DHA:DPA,alternatively no more than 5:1 of DHA:DPA, alternatively no more than3:1 of DHA:DPA, alternatively no more than 2:1 of DHA:DPA, alternativelyno more than 1:1 of DHA:DPA, alternatively no more than 1:2 of DHA:DPA,alternatively no more than 1:3 of DHA:DPA, alternatively no more than1:5 of DHA:DPA, alternatively no more than 1:8 of DHA:DPA, alternativelyno more than 1:10 of DHA:DPA, alternatively no more than 1:15 ofDHA:DPA, alternatively a relative daily dose of no more than 1:20 ofDHA:DPA.

In further embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3 docosapentaenoic acid (HPA-n3)or its glycerol or ethyl esters and which comprise relatively smallamounts of omega-3 docosahexaenoic acid (DHA-n3), together with a commonor alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such method of treatment provides to a subject in needthereof a common or alternative statin dose together with a dose of atleast 10 mg HPA-N3 per day, alternatively at least 15 mg HPA-N3 per day,alternatively at least 20 mg HPA-N3 per day, alternatively at least 25mg HPA-N3 per day, alternatively at least 30 mg HPA-N3 per day,alternatively at least 40 mg HPA-N3 per day, alternatively at least 50mg HPA-N3 per day, alternatively at least 60 mg HPA-N3 per day,alternatively at least 70 mg HPA-N3 per day, alternatively at least 80mg HPA-N3 per day, alternatively at least 90 mg HPA-N3 per day,alternatively at least 100 mg HPA-N3 per day, alternatively at least 120mg HPA-N3 per day, alternatively at least 150 mg HPA-N3 per day,alternatively at least 160 mg HPA-N3 per day, alternatively at least 180mg HPA-N3 per day, alternatively at least 200 mg HPA-N3 per day,alternatively at least 250 mg HPA-N3 per day, alternatively at least 300mg HPA-N3 per day, alternatively at least 350 mg HPA-N3 per day,alternatively at least 400 mg HPA-N3 per day, alternatively at least 500mg HPA-N3 per day, alternatively at least 600 mg HPA-N3 per day,alternatively at least 800 mg HPA-N3 per day, alternatively at least1000 mg HPA-N3 per day, alternatively at least 1200 mg HPA-N3 per day,alternatively at least 1500 mg HPA-N3 or its glycerol or ethyl estersper day, while providing a relatively small amount of DHA-N3 such thatthe DHA:HPA dose ratio is no more than 15:1 of DHA:HPA, alternatively nomore than 12:1 of DHA:HPA, alternatively no more than 10:1 of DHA:HPA,alternatively no more than 8:1 of DHA:HPA, alternatively no more than5:1 of DHA:HPA, alternatively no more than 3:1 of DHA:HPA, alternativelyno more than 2:1 of DHA:HPA, alternatively no more than 1:1 of DHA:HPA,alternatively no more than 1:2 of DHA:HPA, alternatively no more than1:3 of DHA:HPA, alternatively no more than 1:5 of DHA:HPA, alternativelyno more than 1:8 of DHA:HPA, alternatively no more than 1:10 of DHA:HPA,alternatively no more than 1:15 of DHA:HPA, alternatively a relativedaily dose of no more than 1:20 of DHA:HPA.

In yet other embodiments, the compositions of the present invention,which comprise significant amounts of omega-3-pentaenoic acids or theirglycerol or ethyl esters and which comprise relatively small amounts ofomega-3 docosahexaenoic acid (DHA-n3), together with a common oralternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such methods of treatment provides to a subject in needthereof with a common or alternative statin dose and a dose of at least100 mg omega-3-pentaenoic acids per day, alternatively at least 200 mgomega-3-pentaenoic acids per day, alternatively at least 300 mgomega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6000 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing less than 1900 mg of DHA, alternatively less than 1500mg of DHA, alternatively less than 1200 mg of DHA, alternatively lessthan 1000 mg of DHA, alternatively less than 800 mg of DHA,alternatively less than 700 mg of DHA, alternatively less than 600 mg ofDHA, alternatively less than 500 mg of DHA, alternatively less than 400mg of DHA, alternatively less than 350 mg of DHA, alternatively lessthan 300 mg of DHA, alternatively less than 250 mg of DHA, alternativelyless than 200 mg of DHA, alternatively less than 150 mg of DHA,alternatively less than 120 mg of DHA, alternatively less than 100 mg ofDHA, alternatively less than 80 mg of DHA, alternatively less than 60 mgof DHA, alternatively less than 50 mg of DHA, alternatively less than 40mg of DHA, alternatively less than 30 mg of DHA, alternatively less than25 mg of DHA, alternatively less than 20 mg of DHA or its glycerol orethyl esters per day.

In other embodiments, the compositions of the present invention, whichcomprise significant amounts of omega-3-pentaenoic acids including DPAor their glycerol or ethyl esters and which comprise relatively smallamounts of omega-3 docosahexaenoic acid (DHA-n3), together with a commonor alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such methods of treatment provides to a subject in needthereof with a common or alternative statin dose and a dose of at least100 mg omega-3-pentaenoic acids per day, alternatively at least 200 mgomega-3-pentaenoic acids per day, alternatively at least 300 mgomega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6000 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing a relatively small amount of DHA-N3 such that theDHA:DPA ratio is no more than 15:1 of DHA:DPA, alternatively no morethan 12:1 of DHA:DPA, alternatively no more than 10:1 of DHA:DPA,alternatively no more than 8:1 of DHA:DPA, alternatively no more than5:1 of DHA:DPA, alternatively no more than 3:1 of DHA:DPA, alternativelyno more than 2:1 of DHA:DPA, alternatively no more than 1:1 of DHA:DPA,alternatively no more than 1:2 of DHA:DPA, alternatively no more than1:3 of DHA:DPA, alternatively no more than 1:5 of DHA:DPA, alternativelyno more than 1:8 of DHA:DPA, alternatively no more than 1:10 of DHA:DPA,alternatively no more than 1:15 of DHA:DPA, alternatively a relativeamount of no more than 1:20 of DHA:DPA

In yet other embodiments, the compositions of the present invention,which comprise significant amounts of omega-3-pentaenoic acids includingHPA or their glycerol or ethyl esters and which comprise relativelysmall amounts of omega-3 docosahexaenoic acid (DHA-n3), together with acommon or alternative statin dose, may be used for the treatment ofhypertriglyceridemia (either TG≧500 mg/dL, TG≧200 mg/dL, TG≧150 mg/dL,TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499 mg/dL, or TG 150-199mg/dL), mixed dyslipidemia, or any other diseases or medical conditionsspecified above. Such methods of treatment provides to a subject in needthereof with a common or alternative statin dose and a dose of at least100 mg omega-3-pentaenoic acids per day, alternatively at least 200 mgomega-3-pentaenoic acids per day, alternatively at least 300 mgomega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6000 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing a relatively small amount of DHA-N3 such that theDHA:HPA ratio is no more than 15:1 of DHA:HPA, alternatively no morethan 12:1 of DHA:HPA, alternatively no more than 10:1 of DHA:HPA,alternatively no more than 8:1 of DHA:HPA, alternatively no more than5:1 of DHA:HPA, alternatively no more than 3:1 of DHA:HPA, alternativelyno more than 2:1 of DHA:HPA, alternatively no more than 1:1 of DHA:HPA,alternatively no more than 1:2 of DHA:HPA, alternatively no more than1:3 of DHA:HPA, alternatively no more than 1:5 of DHA:HPA, alternativelyno more than 1:8 of DHA:HPA, alternatively no more than 1:10 of DHA:HPA,alternatively no more than 1:15 of DHA:HPA, alternatively a relativeamount of no more than 1:20 of DHA:HPA. In further embodiments, thecompositions of the present invention, which comprise significantamounts of omega-3-pentaenoic acids or their glycerol or ethyl estersand which comprise relatively small amounts of omega-3 docosahexaenoicacid (DHA-n3), together with a common or alternative statin dose, may beused for the treatment of hypertriglyceridemia (either TG≧500 mg/dL,TG≧200 mg/dL, TG≧150 mg/dL, TG 200-499 mg/dL, TG300-499 mg/dL, TG350-499mg/dL, or TG 150-199 mg/dL), mixed dyslipidemia, or any other diseasesor medical conditions specified above.

Such methods of treatment provides to a subject in need thereof with acommon or alternative statin dose and a dose of at least 100 mgomega-3-pentaenoic acids per day, alternatively at least 200 mgomega-3-pentaenoic acids per day, alternatively at least 300 mgomega-3-pentaenoic acids per day, alternatively at least 500 mgomega-3-pentaenoic acids per day, alternatively at least 700 mgomega-3-pentaenoic acids per day, alternatively at least 900 mgomega-3-pentaenoic acids per day, alternatively at least 1000 mgomega-3-pentaenoic acids per day, alternatively at least 1500 mgomega-3-pentaenoic acids per day, alternatively at least 1900 mgomega-3-pentaenoic acids per day, alternatively at least 2000 mgomega-3-pentaenoic acids per day, alternatively at least 2500 mgomega-3-pentaenoic acids per day, alternatively at least 2900 mgomega-3-pentaenoic acids per day, alternatively at least 3000 mgomega-3-pentaenoic acids per day, alternatively at least 3500 mgomega-3-pentaenoic acids per day, alternatively at least 3900 mgomega-3-pentaenoic acids per day, alternatively at least 4000 mgomega-3-pentaenoic acids per day, alternatively at least 4100 mgomega-3-pentaenoic acids per day, alternatively at least 4500 mgomega-3-pentaenoic acids per day, alternatively at least 5000 mgomega-3-pentaenoic acids per day, alternatively at least 5500 mgomega-3-pentaenoic acids per day, alternatively at least 6000 mgomega-3-pentaenoic acids per day or their glycerol or ethyl esters,while providing a relatively small amount of DHA-N3 as compared to theamount of omega-3-pentaenoic acids (N-3-5enoicFA) such that theDHA:N3-5enoic FA ratio is no more than 15:1 of DHA:N3-5enoicFA,alternatively no more than 12:1 of DHA:N3-5enoic FA, alternatively nomore than 10:1 of DHA:N3-5enoic FA, alternatively no more than 8:1 ofDHA:N3-5enoic FA, alternatively no more than 5:1 of DHA:N3-5enoic FA,alternatively no more than 3:1 of DHA:N3-5enoic FA, alternatively nomore than 2:1 of DHA:N3-5enoic FA, alternatively no more than 1:1 ofDHA:N3-5enoic FA, alternatively no more than 1:2 of DHA:N3-5enoicFA,alternatively no more than 1:3 of DHA:N3-5enoic FA, alternatively nomore than 1:5 of DHA:N3-5enoic FA, alternatively no more than 1:8 ofDHA:N3-5enoic FA, alternatively no more than 1:10 of DHA:N3-5enoic FA,alternatively no more than 1:15 of DHA:N3-5enoic FA, alternatively arelative amount of no more than 1:20 of DHA:N3-5enoic FA.

In some embodiments, the composition of the present invention furthercomprises TPA at concentration of at least 0.05%. In some embodiments,the TPA concentration is about 0.01% to about 5%, alternatively about0.05% to about 2%, alternatively about 0.1% to about 1%, alternativelyabout 0.2% to about 0.8%, alternatively about 0.4% to about 0.6%,alternatively about 0.5%.

The compositions of the present invention may also be taken as a generalnutritional supplement.

On a EPA daily dose basis, the compositions of the present invention arepreferably provided in a dose of between 100 mg and 10,000 mg/day,alternatively between 200 mg and 8,000 mg/day, alternatively between 300mg and 6,000 mg/day, alternatively between 400 mg and 5,000 mg/day,alternatively between 500 mg and 4,000 mg/day.

In some embodiments, the compositions of the present invention areprovided in a dose of between about 1000 mg/day to about 5000 mg/day,alternatively about 1200 mg/day to about 3000 mg/day, alternativelyabout 1500 mg/day to about 2500 mg/day, alternatively 1600 mg/day toabout 1950 mg/day, alternatively about 1735 mg/day to about 1855 mg/day,alternatively about 1740 mg/day to about 1840 mg/day, alternativelyabout 1745 mg/day to about 1820 mg/day, alternatively about 1750 mg/dayto about 1800 mg/day, alternatively about 1755 mg/day to about 1790mg/day, alternatively about 1760 mg/day to about 1780 mg/day,alternatively about 1770 mg/day of EPA. In some embodiments, thecompositions of the present invention are provided in a dose of betweenabout 2300 mg/day to about 3000 mg/day, alternatively about 2400 mg/dayto about 2800 mg/day, alternatively about 2520 mg/day to about 2780mg/day, alternatively about 2600 mg/day to about 2700 mg/day,alternatively about 2610 mg/day to about 2680 mg/day, alternativelyabout 2620 mg/day to about 2670 mg/day, alternatively about 2630 mg/dayto about 2665 mg/day, alternatively about 2640 mg/day to about 2660mg/day, alternatively about 2650 mg/day of EPA. In some embodiments, thecompostions of the present invention are provided in a dose of betweenabout 3200 mg/day to about 3900 mg/day, alternatively 3300 mg/day toabout 3800 mg/day, alternatively 3360 mg/day to about 3710 mg/day,alternatively about 3400 mg/day to about 3700 mg/day, alternativelyabout 3450 mg/day to about 3650 mg/day, alternatively about 3500 mg/dayto about 3600 mg/day, alternatively about 3530 mg/day to about 3580mg/day, alternatively about 3540 mg/day to about 3560 mg/day,alternatively about 3550 mg/day of EPA.

In some embodiments, the compositions of the present invention areprovided in a dose of between about 1650 mg/day to about 2050 mg/day,alternatively about 1700 mg/day to about 2000 mg/day, alternativelyabout 1750 mg/day to about 1950 mg/day, alternatively about 1775 mg/dayto about 1925 mg/day, alternatively about 1800 mg/day to about 1900mg/day, alternatively about 1800 mg/day to about 2000 mg/day,alternatively about 1820 mg/day to about 1880 mg/day, alternativelyabout 1830 mg/day to about 1870 mg/day, alternatively about 1840 mg/dayto about 1860 mg/day, alternatively about 1850 mg/day of EPA. In someembodiments, the compostions of the present invention are provided in adose of between about 2500 mg/day to about 3100 mg/day, alternativelyabout 2600 mg/day to about 2000 mg/day, alternatively about 2650 mg/dayto about 2950 mg/day, alternatively about 2700 mg/day to about 2900mg/day, alternatively about 2725 mg/day to about 2875 mg/day,alternatively about 2750 mg/day to about 2850 mg/day, alternativelyabout 2780 mg/day to about 2820 mg/day, alternatively about 2790 mg/dayto about 2810 mg/day, alternatively about 2800 mg/day of EPA. In someembodiments, the compostions of the present invention are provided in adose of between about 3300 mg/day to about 4000 mg/day, alternativelyabout 3400 mg/day to about 3900 mg/day, alternatively about 3500 mg/dayto about 3900 mg/day, alternatively about 3550 mg/day to about 3850mg/day, alternatively about 3600 mg/day to about 3800 mg/day,alternatively about 3650 mg/day to about 3750 mg/day, alternativelyabout 3680 mg/day to about 3725 mg/day, alternatively about 3690 mg/dayto about 3710 mg/day, alternatively about 3700 mg/day of EPA.

In some embodiments, the compositions of the present invention areprovided in a dose of between about 1500 mg/day to about 2500 mg/day,alternatively about 1750 mg/day to about 2300 mg/day, alternativelyabout 1800 mg/day to about 2200 mg/day, alternatively about 1900 mg/dayto about 2100 mg/day, alternatively about 1950 mg/day to about 2050mg/day, alternatively about 1975 mg/day to about 2025 mg/day,alternatively about 2000 mg/day of EPA. In some embodiments, thecompositions of the present invention are provided in a dose of betweenabout 2500 mg/day to about 3500 mg/day, alternatively about 2700 mg/dayto about 3300 mg/day alternatively about 2750 mg/day to about 3300mg/day, alternatively about 2800 mg/day to about 3200 mg/day,alternatively about 2900 mg/day to about 3100 mg/day, alternativelyabout 2950 mg/day to about 3050 mg/day, alternatively about 2975 mg/dayto about 3025 mg/day, alternatively about 3000 mg/day of EPA. In someembodiments, the compositions of the present invention are provided in adose of between about 3500 mg/day to about 4500 mg/day, alternativelyabout 3700 mg/day to about 4300 mg/day, alternatively about 3750 mg/dayto about 4300 mg/day, alternatively about 3800 mg/day to about 4200mg/day, alternatively about 3900 mg/day to about 4100 mg/day,alternatively about 3950 mg/day to about 4050 mg/day, alternativelyabout 3975 mg/day to about 4025 mg/day, alternatively about 4000 mg/dayof EPA.

On a EPA+DPA daily dose basis, the compositions of the present inventionare preferably provided in a dose of between 100 mg and 10,100 mg/day,alternatively between 200 mg and 8,100 mg/day, alternatively between 300mg and 6,100 mg/day, alternatively between 400 mg and 5,100 mg/day,alternatively between 500 mg and 4,100 mg/day.

On a EPA+HPA+DPA daily dose basis, the compositions of the presentinvention are preferably provided in a dose of between 100 mg and 10,100mg/day, alternatively between 200 mg and 8,100 mg/day, alternativelybetween 300 mg and 6,100 mg/day, alternatively between 400 mg and 5,100mg/day, alternatively between 500 mg and 4,100 mg/day.

On an omega-3-pentaenoic acid daily dose basis, the compositions of thepresent invention are preferably provided in a dose of between 100 mgand 10,100 mg/day, alternatively between 200 mg and 8,100 mg/day,alternatively between 300 mg and 6,100 mg/day, alternatively between 400mg and 5,100 mg/day, alternatively between 500 mg and 4,100 mg/day.

The formulation may be a single daily dose preparation to give in onedose the above intakes, or may be in convenient divided doses, forexample, a daily dose formed of two to four soft gelatin or other dosageforms, each containing 300-1500 mg of EPA, EPA+DPA, EPA+DPA+HPA, oromega-3-pentaenoic acids in any form embodied in the present invention.

Flavourants or emulsifiers may be included, for instance, to make thepreparation palatable. Other conventional additives, diluents andexcipients may be present. The preparation for ingestion may be in theform of a capsule, a dry powder, a tablet, a solution, an oil, anemulsion or any other appropriate form. The capsules may be hard or softgelatin capsules, agar capsules, or any other appropriate capsule.

Use of the formulations of the invention in the manufacture of amedicament for the treatment or prevention of any disease or disorder,including those mentioned above, is included in the present invention.

The omega-3 fatty acid composition optionally includes chemicalantioxidants, such as alpha tocopherol, which are administered in pureform or suspended in a vegetable oil, such as soybean oil or corn oil.

The blended fatty acid compositions may then be incorporated into anyappropriate dosage form for oral, enteral, parenteral, rectal, vaginal,dermal or other route of administration. Soft or hard gelatin capsules,flavoured oil blends, emulsifiers or other liquid forms, andmicroencapsulate powders or other dry form vehicles are all appropriateways of administering the products.

The formulated final drug product containing the omega-3 fatty acidcomposition may be administered to a mammal or patient in need thereofin a capsule, a tablet, a powder that can be dispersed in a beverage, oranother solid oral dosage form, a liquid, a soft gel capsule or otherconvenient dosage form such as oral liquid in a capsule, as known in theart. In some embodiments, the capsule comprises a hard gelatin. Thecombination product may also be contained in a liquid suitable forinjection or infusion.

Example pharmaceutical grade finished dosage forms: (a) Soft or hardgelatin capsules each containing 500 mg or 1000 mg of a mix 20 parts ofEPA as a free fatty acid to 1 parts of DPA as a free fatty acid; (b) Asin (a) but where the EPA and DPA free fatty acids are replaced with thefatty acids in any other appropriate bioassimilable form such as theethyl esters; (c) As in (a)-(b) but where the material is in the form ofa microencapsulated powder which can be used as a powder or compressedinto tablets. Such powders may be prepared by a variety of technologiesknown to those skilled in the art; (d) As in (a)-(b) but where theformulation is a liquid or emulsion, appropriately flavoured forpalatable oral administration; (e) As in (a)-(b) but where the materialis formulated into a pharmaceutically acceptable vehicle appropriate fortopical application such as a cream or ointment.

The omega-3 compositions of the present invention may also beadministered with a combination of one or more non-active pharmaceuticalingredients (also known generally herein as “excipients”). Non-activeingredients, for example, serve to solubilize, suspend, thicken, dilute,emulsify, stabilize, preserve, protect, color, flavor, and fashion theactive ingredients into an applicable and efficacious preparation thatis safe, convenient, and otherwise acceptable for use. Thus, thenon-active ingredients may include colloidal silicon dioxide,crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose,polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearylfumarate, talc, titanium dioxide and xanthum gum.

The term “pharmaceutically acceptable vehicle,” as used herein, includesany of the following: a solution where the first API and optional otheringredients are wholly dissolved in a solubilizer (e.g., apharmaceutically acceptable solvent or mixture of solvents), wherein thesolution remains in clear liquid form at about room temperature; asuspension; an oil; or a semi-solid, wherein the first API andoptionally other ingredients are dissolved wholly or partially in asolubilizer (an emulsion, cream, etc.).

A “pharmaceutical grade finished dosage form” as used herein may beconstrued as a unit dose form suitable for administration to, forexample, human or animal subjects, and having content uniformityacceptable to regulatory authorities. For example, under the USPrequirements for content uniformity, a pharmaceutical grade finisheddosage form should have an amount of API within the range of 85% to 115%of the desired dosage and an RSD less than or equal to 6.0%. Inaddition, a pharmaceutical grade finished dosage form must be stable(i.e., have a “shelf life”) for a pharmaceutically acceptable durationof time, preferably at least six months, alternatively at least oneyear, or at least two years, when stored at room temperature (about 23degree Celcius to 27 degree Celcius, preferably about 25 degree Celcius)and 60% relative humidity. Typically, stability is determined byphysical appearance and/or chemical modification of the ingredients, inaccordance with standards well-known in the pharmaceutical arts,including those documented in ICH guidelines.

The omega-3 fatty acid dosage form optionally includes chemicalantioxidants, such as alpha tocopherol, oils, such as soybean oil andpartially hydrogenated vegetable oil, and lubricants such asfractionated coconut oil, lecithin and a mixture of the same.

EXAMPLES Example 1

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 98:2 the intermediates MEGAPEX E90D00EE(90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (≧95% DPA synthetic fattyacid produced from EPA ethyl ester concentrate) converted to ethylester, respectively. These intermediates were prepared and commerciallyoffered for sale by Chemport Korea (MEGAPEX) and Equateq Ltd fromScotland, UK (MAXOMEGA). The relative amounts of fatty acids present inthe starting intermediates and in the resulting novel composition arelisted in Table 1 below. The resulting novel composition comprises89.10% EPA, 1.95% DPA, 0.19% HPA, 91.24% omega-3-pentaenoic acids, lessthan 0.01% DHA, 91.24% omega-3-pentaenoic acids, 93.09% total omega-3fatty acids, 3.15% ARA and 3.57% omega-6 fatty acids (all Area %).

TABLE 1 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 1 98.0% 2.0% Megapex Maxomega NovelFatty Acid E90D00EE DPA95FFA => EE Composition c18:0 0.05 0 0.05 c18:1n90.06 0 0.06 c18:1n7 0.02 0 0.02 c18:2n6 0.01 0 0.01 c18:3n6 0.02 0 0.02c18:3n3 0.03 0 0.03 c18:4n3 0.42 0 0.41 c18:4n1 0.07 0 0.07 c20:0 0 00.00 c20:1n11 0 0 0.00 c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0.25 00.25 c20:3n9 0 0 0.00 c20:3n6 0.15 0 0.15 c21:0 0 0 0.00 c20:4n6 3.21 03.15 c20:3n3 0 0 0.00 c20:4n3 1.44 0 1.41 c20:5n3 90.92 0 89.10 c22:00.3 0 0.29 c22:1n11 0.07 0 0.07 c22:1n9 0.18 0 0.18 c22:1n7 0.19 0 0.19c21:5n3 0.19 0 0.19 c22:5n6 0 0 0.00 c22:5n3 0 97.27 1.95 c22:6n3 0 00.00 c24:0 0 0.33 0.01 OTHER 2.42 2.4 2.42 100 100 100

Example 2

A composition according to the present prevention is prepared by mixingand homogenizing in a ratio of 96:4 the intermediates MEGAPEX E90D00EE(90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (≧95% DPA synthetic fattyacid produced from EPA ethyl ester concentrate), converted to ethylester, respectively. These intermediates were prepared and commerciallyoffered for sale by Chemport Korea (MEGAPEX) and Equateq Ltd fromScotland, UK (MAXOMEGA). The relative amounts of fatty acids present inthe starting intermediates and in the resulting novel composition islisted in Table 2 below. The resulting novel composition comprises87.28% EPA, 3.89% DPA, 0.18% HPA, 91.35% omega-3-pentaenoic acids, lessthan 0.01% DHA, 93.17% total omega-3 fatty acids and 3.49% omega-6 fattyacids (all Area %).

TABLE 2 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 2 96.0% 4.0% Megapex Maxomega NovelFatty Acid E90D00EE DPA95FFA => EE Composition c18:0 0.05 0 0.05 c18:1n90.06 0 0.06 c18:1n7 0.02 0 0.02 c18:2n6 0.01 0 0.01 c18:3n6 0.02 0 0.02c18:3n3 0.03 0 0.03 c18:4n3 0.42 0 0.40 c18:4n1 0.07 0 0.07 c20:0 0 00.00 c20:1n11 0 0 0.00 c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0.25 00.24 c20:3n9 0 0 0.00 c20:3n6 0.15 0 0.14 c21:0 0 0 0.00 c20:4n6 3.21 03.08 c20:3n3 0 0 0.00 c20:4n3 1.44 0 1.38 c20:5n3 90.92 0 87.28 c22:00.3 0 0.29 c22:1n11 0.07 0 0.07 c22:1n9 0.18 0 0.17 c22:1n7 0.19 0 0.18c21:5n3 0.19 0 0.18 c22:5n6 0 0 0.00 c22:5n3 0 97.27 3.89 c22:6n3 0 00.00 c24:0 0 0.33 0.01 OTHER 2.42 2.4 2.42 100 100 100

Example 3

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 94:6 the intermediates MEGAPEX E90D00EE(90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (≧95% DPA synthetic fattyacid produced from EPA ethyl ester concentrate) converted to ethylester, respectively. These intermediates were prepared and commerciallyoffered for sale by Chemport Korea (MEGAPEX) and Equateq Ltd fromScotland, UK (MAXOMEGA). The relative amounts of fatty acids present inthe starting intermediates and in the resulting novel composition arelisted in table 3 below. The resulting novel composition comprises85.46% EPA, 5.84% DPA, 0.18% HPA, 91.48% omega-3-pentaenoic acids, lessthan 0.01% DHA, 93.26% total omega-3 fatty acids, 3.02% ARA, and 3.42%omega-6 fatty acids (all Area %).

TABLE 3 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 3 94.0% 6.0% Megapex Maxomega NovelFatty Acid E90D00EE DPA95FFA => EE Composition c18:0 0.05 0 0.05 c18:1n90.06 0 0.06 c18:1n7 0.02 0 0.02 c18:2n6 0.01 0 0.01 c18:3n6 0.02 0 0.02c18:3n3 0.03 0 0.03 c18:4n3 0.42 0 0.39 c18:4n1 0.07 0 0.07 c20:0 0 00.00 c20:1n11 0 0 0.00 c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0.25 00.24 c20:3n9 0 0 0.00 c20:3n6 0.15 0 0.14 c21:0 0 0 0.00 c20:4n6 3.21 03.02 c20:3n3 0 0 0.00 c20:4n3 1.44 0 1.35 c20:5n3 90.92 0 85.46 c22:00.3 0 0.28 c22:1n11 0.07 0 0.07 c22:1n9 0.18 0 0.17 c22:1n7 0.19 0 0.18c21:5n3 0.19 0 0.18 c22:5n6 0 0 0.00 c22:5n3 0 97.27 5.84 c22:6n3 0 00.00 c24:0 0 0.33 0.02 OTHER 2.42 2.4 2.42 100 100 100

Example 4

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 75:25 the intermediates MEGAPEX E90D00EE(90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (≧95% DPA synthetic fattyacid produced from EPA ethyl ester concentrate, converted to ethylester, respectively. These intermediates were prepared and commerciallyoffered for sale by Chemport Korea (MEGAPEX) and Equateq Ltd fromScotland, UK (MAXOMEGA). The relative amounts of fatty acids present inthe starting intermediates and in the resulting novel composition islisted in table 4 below. The resulting novel composition comprises68.10% EPA, 24.32% DPA, 0.19% HPA, 92.65% omega-3-pentaenoic acids, lessthan 0.01% DHA, 94.07% total omega-3 fatty acids, 2.41% ARA and 2.73%omega-6 fatty acids (all Area %).

TABLE 4 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 4 75.0% 25.0% Megapex Maxomega NovelFatty Acid E90D00EE DPA95FFA => EE Composition c18:0 0.05 0 0.04 c18:1n90.06 0 0.05 c18:1n7 0.02 0 0.02 c18:2n6 0.01 0 0.01 c18:3n6 0.02 0 0.02c18:3n3 0.03 0 0.02 c18:4n3 0.42 0 0.32 c18:4n1 0.07 0 0.05 c20:0 0 00.00 c20:1n11 0 0 0.00 c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0.25 00.19 c20:3n9 0 0 0.00 c20:3n6 0.15 0 0.11 c21:0 0 0 0.00 c20:4n6 3.21 02.41 c20:3n3 0 0 0.00 c20:4n3 1.44 0 1.08 c20:5n3 90.92 0 68.19 c22:00.3 0 0.23 c22:1n11 0.07 0 0.05 c22:1n9 0.18 0 0.14 c22:1n7 0.19 0 0.14c21:5n3 0.19 0 0.14 c22:5n6 0 0 0.00 c22:5n3 0 97.27 24.32 c22:6n3 0 00.00 c24:0 0 0.33 0.08 OTHER 2.42 2.4 2.42 100 100 100

Example 5

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 60:40 the intermediates KD-PharmaKD-PUR900EE and MAXOMEGA DPA95 FFA converted to ethyl ester, respectively.These intermediates were prepared and commercially offered for sale byKD-Pharma Germany (KD-Pharma) and Equateq Ltd from Scotland, UK(MAXOMEGA). The relative amounts of fatty acids present in the startingintermediates and in the resulting novel composition is listed in table5 below. The resulting novel composition comprises 55.74% EPA, 39.26%DPA, 2.39% HPA, 97.44% omega-3-pentaenoic acids, and 98.06% totalomega-3 fatty acids (all Area %).

TABLE 5 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 5 60.0% 40.0% KD-Pur Maxomega NovelFatty Acid 900EE DPA95FFA => EE Composition c18:0 0 0 0.00 c18:1n9 0 00.00 c18:1n7 0 0 0.00 c18:2n6 0 0 0.00 c18:3n6 0 0 0.00 c18:3n3 0 0 0.00c18:4n3 0 0 0.00 c18:4n1 0 0 0.00 c20:0 0 0 0.00 c20:1n11 0 0 0.00c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0 0 0.00 c20:3n9 0 0 0.00c20:3n6 0 0 0.00 c21:0 0 0 0.00 c20:4n6 0 0 0.00 c20:3n3 0 0 0.00c20:4n3 1.04 0 0.62 c20:5n3 92.99 0 55.79 c22:0 0 0 0.00 c22:1n11 0 00.00 c22:1n9 0 0 0.00 c22:1n7 0 0 0.00 c21:5n3 3.98 0 2.39 c22:5n6 0 00.00 c22:5n3 0.58 97.27 39.26 c22:6n3 0 0 0.00 c24:0 0 0.33 0.13 OTHER1.41 2.4 1.81 100.00 100 100.00

Example 6

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 96:4 the intermediates KD-PUR 900EEKD-Pharma and MAXOMEGA DPA95 FFA converted to ethyl ester, respectively.These intermediates were prepared and commercially offered for sale byKD-Pharma Germany (KD-Pharma) and Equateq Ltd from Scotland, UK(MAXOMEGA). The relative amounts of fatty acids present in the startingintermediates and in the resulting novel composition is listed in table6 below. The resulting novel composition comprises 89.27% EPA, 4.45%DPA, 3.82% HPA, 97.54% omega-3-pentaenoic acids, and 98.54% totalomega-3 fatty acids (all Area %).

TABLE 6 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 6 96.0% 4.0% KD-Pur Maxomega NovelFatty Acid 900EE DPA95FFA => EE Composition c18:0 0 0 0.00 c18:1n9 0 00.00 c18:1n7 0 0 0.00 c18:2n6 0 0 0.00 c18:3n6 0 0 0.00 c18:3n3 0 0 0.00c18:4n3 0 0 0.00 c18:4n1 0 0 0.00 c20:0 0 0 0.00 c20:1n11 0 0 0.00c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0 0 0.00 c20:3n9 0 0 0.00c20:3n6 0 0 0.00 c21:0 0 0 0.00 c20:4n6 0 0 0.00 c20:3n3 0 0 0.00c20:4n3 1.04 0 1.00 c20:5n3 92.99 0 89.27 c22:0 0 0 0.00 c22:1n11 0 00.00 c22:1n9 0 0 0.00 c22:1n7 0 0 0.00 c21:5n3 3.98 0 3.82 c22:5n6 0 00.00 c22:5n3 0.58 97.27 4.45 c22:6n3 0 0 0.00 c24:0 0 0.33 0.01 OTHER1.41 2.4 1.45 100.00 100 100.00

Example 7

A composition according to the present invention is prepared by mixingand homogenizing in a ratio of 91.8:8.2 the intermediates KD-PUR 910EEKD-Pharma and DPA95 FFA converted to ethyl ester, respectively. Therelative amounts of fatty acids present in the starting intermediatesand in the resulting novel composition is listed in table 7 below.

TABLE 7 Fatty acid Composition (Area %) of intermediates and novelcomposition according to Example 7 91.8% 8.2% KD-Pur DPA - Novel FattyAcid EPA910EE 95% Est compositio N6 N3 c18:0 0 0 0.00 c18:1n9 0 0 0.00c18:1n7 0 0 0.00 c18:2n6 0 0 0.00 0.00 c18:3n6 0 0 0.00 0.00 c18:3n3 0 00.00 0.00 c18:4n3 0 0 0.00 0.00 c18:4n1 0 0 0.00 c20:0 0 0 0.00 c20:1n110.1 0 0.09 c20:1n9 0 0 0.00 c20:1n7 0 0 0.00 c20:2n6 0 0 0.00 0.00c20:2n9 0 0.2 0.02 c20:3n9 0 0 0.00 c20:3n6 0 0 0.00 0.00 c21:0 0 0 0.00c20:4n6 0.3 0 0.28 0.28 c20:3n3 0 0 0.00 0.00 c20:4n3 1.2 0.3 1.13 1.13c20:5n3 92.5 0 85.34 85.34 c22:0 0.2 0 0.18 c22:1n11 0 0 0.00 c22:1n9 00 0.00 c22:1n7 0 0 0.00 c22:4n3 0 1.9 0.16 0.16 c21:5n3 3.3 0.1 3.083.08 c22:5n6 0 0 0.00 0.00 c22:5n3 0.2 97 8.16 8.16 c22:6n3 1.5 0 1.251.25 c24:0 0 0 0.00 OTHER 0.7 0.5 0.68 100.00 100 100.36 0.28 99.11

Example 8

The ethyl ester composition of Example 4 may be converted into a freefatty acid composition with essentially the same fatty acid compositionaccording to “Conversion Method EE to FFA” below. This method isindiscriminate with respect to the type, degree of saturation or lengthof fatty acid if performed for an adequate amount of time under thedescribed conditions.

Conversion Method EE to FFA

-   -   1. Fatty Acid Ethyl Ester (FAEE GMP, approx. 3 mmol/g) oil is        brought into a closed heated/cooled reaction chamber under        nitrogen atmosphere (preferably with pressure control), and        heated to 50-60 degree Celcius under stirring.    -   2. 2M NaOH solution in water is added under firm stirring to        ensure phase mixing (est. 2-3×FAEE w/w) and stir until no ethyl        ester is presence (est. 2-4 hrs). Test ethyl ester presence at        lab scale/in process with TLC (hexanes/EtOAc 9:1) and with EP GC        method to confirm reaction completion under GMP.    -   3. Under cooling (keep mixture below 70 degree Celcius), add 6M        HCl in water (est. <1 hr) until slightly acid (˜pH3-4). It may        be necessary to control pressure to prevent excessive foaming.        Then halt stirring, give time to let phases separate, and remove        water phase from bottom (keep oil protected from oxygen, apply        nitrogen atmosphere blanket).    -   4. Add demineralized water (est. 2-3×FAEE w/w) and wash out NaCl        and ethanol from oil under firm stirring (est. ˜1 hr). Halt        stirring, give time to let phases separate, and remove water        phase from bottom (keep oil protected from oxygen, apply        nitrogen atmosphere blanket).    -   5. Repeat Step 4 several times (˜2×) to remove ethanol and NaCl.    -   6. Remove water and remaining ethanol [determine in-process        controls], confirm under GMP with USP residual solvent method        (target: ethanol<100 ppm) by stirring oil while applying vacuum        10-50 mbar (with solvent trap) and heat oil (70-80 degree        celcius) until water/ethanol target is met (est. 2-4 hrs).    -   7. Add anti-oxidants (i.e. alpha-D-tocopherol, USP, target 4        mg/g) and/or other excipients.    -   8. All reagents and excipients USP grade.

Example 9

The ethyl ester composition of Example 3 is converted into a free fattyacid composition with essentially the same fatty acid compositionaccording to “Conversion Method EE to FFA” above. This method isindiscriminate with respect to the type, degree of saturation or lengthof fatty acid if performed for an adequate amount of time under thedescribed conditions.

Example 10

The ethyl ester composition of Example 6 is converted into a free fattyacid composition with essentially the same fatty acid compositionaccording to “Conversion Method EE to FFA” above. This method isindiscriminate with respect to the type, degree of saturation or lengthof fatty acid if performed for an adequate amount of time under thedescribed conditions.

Example 11

The composition of Example 4 is formulated into a soft gelatin capsule.Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mgalpha-D-tocopherol in one liter of corn oil; corn oil is a triglyceridelow in omega-3) is added to the composition of Example 4, by mixing andhomogenizing 100 mL of this anti-oxidant preparation into 100 liters ofthe oil composition of Example 4 followed by thorough homogenization.The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil isencapsulated into soft gelatin capsules with printed logo according togeneral methods typically used by Accucaps in Canada for fish oils or byany other documented and operational encapsulation method. The fill massof the oil is approximately 1.08 gram/capsule, providing a dose ofapproximately 1000 mg omega-3-pentaenoic-acids ethyl esters per capsule.Finally, the capsules are bottled in HDPE bottles with induction sealand child resistant cap.

Example 12

The composition of Example 9 is formulated into a soft gelatin capsule.Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mgalpha-D-tocopherol in one liter of corn oil; corn oil is a triglyceridelow in omega-3) is added to the composition of Example 4, by mixing andhomogenizing 100 mL of this anti-oxidant preparation into 100 liters ofthe oil composition of Example 4 followed by thorough homogenization.The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil isencapsulated into soft gelatin capsules with printed logo according togeneral methods typically used by Banner in High Point, N.C., for fishoils or by any other documented and operational encapsulation method.The fill mass of the oil is approximately 1.09 gram/capsule, providing adose of approximately 1000 mg omega-3-pentaenoic-acids per capsule.Finally, the capsules are bottled in HDPE bottles with induction sealand child resistant cap.

Example 13

The composition of Example 5 is formulated into a soft gelatin capsule.Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mgalpha-D-tocopherol in one liter of corn oil; corn oil is a triglyceridelow in omega-3) is added to the composition of Example 4, by mixing andhomogenizing 100 mL of this anti-oxidant preparation into 100 liters ofthe oil composition of Example 4 followed by thorough homogenization.The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil isencapsulated into soft gelatin capsules with printed logo according togeneral methods typically used by Catalent in St. Petersburg, Fla., forfish oils or by any other documented and operational encapsulationmethod. The fill mass of the oil is approximately 1.05 gram/capsule,providing a dose of approximately 1000 mg omega-3-pentaenoic-acids ethylesters per capsule. Finally, the capsules are bottled in HDPE bottleswith induction seal and child resistant cap.

Example 14

The composition of Example 10 is formulated into a soft gelatin capsule.Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mgalpha-D-tocopherol in one liter of corn oil; corn oil is a triglyceridelow in omega-3) is added to the composition of Example 4, by mixing andhomogenizing 100 mL of this anti-oxidant preparation into 100 liters ofthe oil composition of Example 4 followed by thorough homogenization.The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil isencapsulated into soft gelatin capsules with printed logo according togeneral methods typically used by Banner in High Point, N.C., for fishoils or by any other documented and operational encapsulation method.The fill mass of the oil is 1.06 gram/capsule, providing a dose ofapproximately 1000 mg omega-3-pentaenoic-acids per capsule. Finally, thecapsules are bottled in HDPE bottles with induction seal and childresistant cap.

Example 15

A patient is diagnosed with severe hypertriglyceridemia (TG>500 mg/dL).Thereupon, the patient may be initiated on daily treatment with one ofthe encapsulated compositions according to Examples 10, 11, 12 or 13.Four capsules per day are administered to this patient (4 g/d).

Example 16

A patient is treated as per Example 15. The treatment results insignificant reduction of TG as well as non-HDL- and VLDL-cholesterollevels while the LDL-cholesterol level changes insignificantly.

Example 17

A patient is treated as per Example 15. The treatment results insignificant reduction of TG as well as non-HDL-, LDL- andVLDL-cholesterol levels.

Example 18

A patient already undergoing treatment with a statin is diagnosed withhigh triglycerides (TG between 200 and 500 mg/dL). Thereupon, thepatient is initiated on daily treatment with one of the encapsulatedcompositions according to Examples 10, 11, 12 or 13. Four capsules perday are administered to this patient (4 g/d).

Example 19

A patient is treated as per Example 18. The treatment results insignificant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 20

A patient is diagnosed with mixed dyslipidemia (TG between 200 and 700mg/dL and LDL-cholesterol above 190 mg/dL). Thereupon, the patient isinitiated on concomitant daily treatment with a statin and one of theencapsulated compositions according to Examples 11, 12, 13, or 14. Fourcapsules per day are administered to this patient (4 g/d).

Example 21

A patient is treated as per Example 20. The treatment results insignificant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 22

A patient is diagnosed with mixed dyslipidemia (TG between 200 and 700mg/dL and non-HDL-cholesterol above 200 mg/dL). Thereupon, the patientis initiated on concomitant daily treatment with a statin and one of theencapsulated compositions according to Examples 11, 12, 13, or 14. Fourcapsules per day are administered to this patient (4 g/d).

Example 23

A patient is treated as per Example 22. The treatment results insignificant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 24

A patient is diagnosed to be at significant risk for a cardiovascularevent according to the NCEP guidelines and has TG levels above 150mg/dL. Thereupon, the patient is initiated on daily treatment with oneof the encapsulated compositions according to Examples 11, 12, 13, or14. Four capsules per day are administered to this patient (4 g/d).

Example 25

A patient is treated as per Example 24. The treatment results insignificant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 26

A patient diagnosed as per Example 15, 18, 20, 22 or 24 is treated with3 capsules per day (instead of 4) of one of the encapsulatedcompositions according to Examples 11, 12, 13, or 14. The treatmentresults in significant reduction of TG as well as non-HDL- andVLDL-cholesterol levels.

Example 27

A patient diagnosed as per Example 15, 18, 20, 22 or 24 is treated with3 capsules per day (instead of 4) of one of the encapsulatedcompositions according to Examples 11, 12, 13, or 14. The treatmentresults in significant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 28

A patient diagnosed as per Example 15, 18, 20, 22 or 24 is treated with2 capsules per day (instead of 3 or 4) of one of the encapsulatedcompositions according to Examples 11, 12, 13, or 14. The treatmentresults in significant reduction of TG as well as non-HDL- andVLDL-cholesterol levels.

Example 29

A patient diagnosed as per Example 15, 18, 20, 22 or 24 is treated with2 capsules per day (instead of 3 or 4) of one of the encapsulatedcompositions according to Examples 11, 12, 13, or 14. The treatmentresults in significant reduction of TG as well as non-HDL-, VLDL- andLDL-cholesterol levels.

Example 30

The following are examples of preferred embodiments of the presentinvention.

Minimum Maximum Target Composition (mg/g) (mg/g) (mg/g) COMPOSITION 1aOmega-3 pentaenoic acid 880 980 930 Eicosapentaenoic acid (EPA) 800 950850 Heneicosapentaenoic acid (HPA) 5 60 30 Docosapentaenoic acid (DPA)60 100 80 Docosahexaenoic acid (DHA) 25 <10 COMPOSITION 1b Omega-3pentaenoic acid 870 990 920 Eicosapentaenoic acid (EPA) 750 950 830Heneicosapentaenoic acid (HPA) 5 70 40 Docosapentaenoic acid (DPA) 50130 90 Docosahexaenoic acid (DHA) 40 20In COMPOSITIONS 1a and 1b, the EPA:HPA ratio is between 13 and 190, theEPA:DPA ratio is between 8 and 15, the HPA:DPA ration between 0.05 and1, the DPA:DHA ratio more than 2.4, preferably more than 4, morepreferably more than 6, most preferably more than 10, and the EPA:DHAratio more than 32, preferably more than 38, more preferably more than80, most preferably more than 95. The EPA, HPA, DPA and DHA may becomposed as a glyceride (such as triglyceride), an ester (such as ethylester), or a free fatty acid.

Example 31

The following is an example of a preferred embodiment of the presentinvention.

COMPOSITION 2 Minimum Maximum Target Composition (mg/g) (mg/g) (mg/g)Omega-3 pentaenoic acid 900 980 940 Eicosapentaenoic acid (EPA) 15 60 30Heneicosapentaenoic acid (HPA) 5 60 30 Docosapentaenoic acid (DPA) 800950 880 Docosahexaenoic acid (DHA) 25 <10In COMPOSITION 2, the EPA:HPA ratio is between 0.25 and 12, the DPA:EPAratio is between 13 and 63, the DPA:HPA ration between 13 and 190, theDPA:DHA ratio more than 32, preferably more than 38, more preferablymore than 80, most preferably more than 95, and the EPA:DHA ratio morethan 00.6, preferably more than 1.5, more preferably more than 2.4, mostpreferably more than 6. The EPA, HPA, DPA and DHA may be composed as aglyceride (such as triglyceride), an ester (such as ethyl ester), or afree fatty acid.

Example 32

The following is an example of an embodiment of the present invention.

COMPOSITION 3 Minimum Maximum Target Composition (mg/g) (mg/g) (mg/g)Docosapentaenoic acid (DPA n-3) 800 990 920The DPA may be composed as a glyceride (such as triglyceride), an ester(such as ethyl ester), or a free fatty acid.

Example 33

The following is an example of an embodiment of the present invention.

COMPOSITION 4 Minimum Maximum Target Composition (mg/g) (mg/g) (mg/g)Omega-3 pentaenoic acid 930 1000 966 Eicosapentaenoic acid (EPA) 840 870853 Heneicosapentaenoic acid (HPA) 20 40 30 Docosapentaenoic acid (DPA)60 100 81 Docosahexaenoic acid (DHA) 5 20 12

Example 34

A mixture of DPA and EPA was prepared by combining 1 g DPA Ethyl Ester(SE-133-III) with 10 g EPA Ethyl Ester, 914 mg/g (KD Pharma FM13001) in150 ml of 95% ethanol/water containing 35 ml of 2M sodium hydroxide.This reaction mixture was stirred overnight at ambient temperature. Tlcanalysis showed complete conversion of the ethyl esters to thecorresponding acids. The reaction mixture was cooled in an ice bath,acidified with 6N hydrochloric acid and concentrated on a rotavap underreduced pressure. Water and ethyl acetate were added, the phasesseparated and the aqueous residue extracted with ethyl acetate. Theethyl acetate extracts were combined, dried over sodium sulfate andconcentrated to dryness on a rotavap under reduced pressure. Yield: 9.83g. The ethyl ester mixture was then converted to the free fatty acids asdescribed in example 7.

A representative sample of this ethyl ester composition was analysedusing split inject by capillary gas chromatography by a 30 meter×0.25 mmRestek Stabil wax column using temperature programming.

Example 35

The following describes a study conducted to determine the effect ofcompositions of the present invention.

An n-3 Pentaenoic testing batch containing roughly 85% EPA, 8% DPA, and1% HPA was used to study pharmacodynamic effects in the Charles RiverZucker fa/fa non-diabetic rat (strain code 185), which is known todisplay characteristics of insulin resistance, glucose intolerance,hyperinsulinemia, obesity and dyslipidemia. VASCEPA© is also used as acomparator. Male, eight to nine week old animals were used, with eightrats (n=8) per group. At the initiation of daily dosing, all animalswere placed on chow+0.5% cholesterol diet (D13022002: Research Diets,New Brunswick, N.J.). Corn oil was used as a diluent for the omega-3compounds, and methylcellulose to prepare the statin (atorvastatin) fordosing. A separate group of animals receiving corn oil alone was used asthe untreated control group. Animals received daily doses of respectivesolutions by oral gavage. The study was conducted in 2 phases. In thefirst phase, the n-3 Pentaenoic composition and VASCEPA© solution isadministered at 200 mg/kg, 400 mg/kg, and 1000 mg/kg. Animals were doseddaily for 14 days. For reference, a rat dose of 400 mg/kg would beequivalent to a human daily dose of approximately 4 grams (as shown inReagan-Shaw et al. “Dose translation from animal to human studiesrevisited,” FASEB J. 22, 659-661 (2007), which is incorporated byreference in its entirety).

The second phase was initiated on day 15, with the groups receiving then-3 Pentaenoic composition and VASCEPA© 400 mg/kg solution beingco-administered statin at 10 mg/kg. Another group, previously dosed withcorn oil vehicle, received atorvastatin to serve as an appropriatecontrol. This second phase consisted of 14 days of daily, oraladministration.

Plasma total cholesterol, LDL, HDL, triglycerides and VLDL were measuredin the fasting state on day 0, 7 and 14; and for those groups includedin the second phase on days 21 and 28. Levels of lipid parameters weredetermined in a 96-well multiplexed system using standard clinicalchemistry techniques. Non-HDL cholesterol was calculated by subtractingthe HDL value from the total cholesterol value. In addition, for thegroups included in the second phase, insulin levels were determined atday 28. FIG. 1 shows the fasting plasma lipid values after seven days ofdosing. FIG. 2 shows the fasting plasma insulin levels after 28 days ofadministration.

Expression of genes for HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A;key regulatory enzyme for new cholesterol biosynthesis), PCSK9(pro-protein convertase subtilisin kexin 9; associated with LDL receptorfunctioning and increased levels of LDL), and SREB-2 (sterol regulatoryenhancing binding protein 2; regulates transcription of a wide varietyof genes involved with new cholesterol synthesis) are evaluated in liverfrom groups included in the second phase. The mRNA (messenger RNA) wasisolated from samples previously frozen at −70° C.s, and cDNA(complementary DNA) is derived for further study using standardmolecular biology technique. Samples and corresponding probes for genesof interest are loaded onto a Life Science TLDA card. The level of geneexpression was quantified using real time RT-PCR (reverse transcriptasepolymerase chain reaction) and calculated using the ΔΔCt techniquerelative to the vehicle group in accordance to methodology recommendedand as described by Applied Biosystems (Guide to Performing RelativeQuantitation of Gene Expression Using Real-Time Quantitative PCR). FIG.3 shows the relative liver gene expression following 28 days ofadministration.

Example 36

The following describes a study to determine the effect of compositionsof the present invention.

Study #2—Humans

The overall pharmacokinetics of one of COMPOSITION 1a, 1b, 2, 3, or 4are evaluated versus a reference compound after administration underfasting or fed conditions in normal, mostly healthy volunteers in astandard, 4-way cross-over trial design format. VASCEPA®, EPANOVA™,LOVAZA®, or EPADEL® are used as a reference compound. A total of 48subjects are separated into 2 groups of 24. Each subject serves as hisor her own internal control for comparison purposes under this 4-waycrossover design. Inclusion criteria for tested subjects includevolunteers between ages 18-65, with a BMI of 30-35 (alternatively a BMIof 27-35) and triglyceride levels less than 350 mg/dL, who consume nomore than 1 fish meal per week and who are not currently prescribedpharmaco-therapy for lowering triglycerides, including but not limitedto fibrates, omega-3 agents, and niacin. Volunteers on stableanti-hypertensive, anti-diabetic and thyroid therapy are allowed forconsideration. Any person on stable statin therapy is considered iftheir triglyceride levels are less than 350 mg/dL. However, the totalcomposition of subjects in the study with this particular profile islimited to no more than 30%.

Volunteers self-administering omega-3 non-prescription dietarysupplements are asked to refrain from their use 2 weeks prior to theinitiation of the study until study completion.

Pharmacokinetic Study#2 Design

The effect of oral administration of the compounds tested in this studyis evaluated under fed versus fasting administration conditions, inorder to determine drug pharmacokinetics, as well as to understand theeffects of food on drug pharmacokinetics. COMPOSITION 1a or 1b or thereference compound are dosed at approximately 4 grams/day in the morningby administration of 4 capsules containing approximately 1 gram of eachcompound. Several days prior to pharmacokinetic evaluations, volunteersare housed at the testing facility in order to ensure well-controlledexperimental conditions.

Compounds are given to volunteers following an overnight fast, withplasma samples obtained prior to dosing and at various time points afterday 1 and day 14 dosing. Volunteers are allowed access to water, andwell-defined meals at certain times. Afterwards, compound administrationis stopped for a 2-4 week washout period, and the groups are switchedwith respect to which compound they would receive, meaning that thegroup initially receiving COMPOSITION 1a or 1b is switched to receivethe reference compound, and vice versa. Fasting pharmacokinetics aredetermined using the procedure described above. Following completion ofthe second 14-day dosing cycle, compound dosing is stopped for a2-4-week washout period prior to the initiation of the a similar cycleas above, now with COMPOSITION 1a or 1b and the reference compound areadministered together with a meal.

Plasma levels of omega-3 fatty acids of interest from the study aredetermined utilizing an analytical LC/MS technique under GLP laboratoryconditions in order to determine Cmax, Tmax and AUC for the omega-3fatty acids of interest, including EPA, DPA, HPA, DHA, and other omega-3fatty acids.

Results

The results of the study show that COMPOSITION 1a or 1b has a betterbioavailability (as measured by AUC and Cmax) than the referencecompound. This effect is seen under fasting and/or fed administrationconditions.

In an alternate study design, this Study #2 is conducted with a certaindose level of COMPOSITION 2, COMPOSITION 3, or COMPOSITION 4 instead ofCOMPOSITION 1.

Example 37

The following describes a study (STUDY #3) to determine the effect ofcompositions of the present invention.

A Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-WeekStudy to Evaluate the Efficacy and Safety of COMPOSITION 1a, 1b, 2, 3 or4 in Patients With Fasting Triglyceride Levels ≧500 mg/dL and ≧2000mg/dL:

This Phase 3, multi-center study consists of a 6- to 8-weekscreening/washout period (to include a diet and lifestyle stabilizationperiod), which includes a fasting triglyceride (TG) qualifying period of2-3 weeks, followed by a 12-week double-blind treatment period. Patientson statin therapy (with or without ezetimibe) at screening are evaluatedby the investigator as to whether this therapy could be safelydiscontinued at screening, or if it is to be continued. Patients on anyother dyslipidemia therapy need to discontinue these in order to qualifyfor the study. If statin therapy (with or without ezetimibe) is to becontinued, dose(s) must be stable for ≧4 weeks prior to the fasting TGbaseline qualifying measurements for randomization. The screening visitis to occur at either 6 weeks before randomization for patients not onlipid-altering therapy at screening or for patients who do not need todiscontinue their current dyslipidemia therapy, or at 8 weeks beforerandomization for patients who require washout of their currentdyslipidemia therapy at screening.

The population for this study is men and women >18 years of age with abody mass index (BMI) ≦45 kg/m2. Patients on lipid-lowering therapy andpatients not on lipid-lowering therapy are eligible to enroll in thestudy. Patients had to have an average TG level ≧500 mg/dL and ≦2000mg/dL during the screening period to be eligible for randomization.

After confirmation of qualifying fasting TG values, eligible patientswill enter a 12-week randomized, double-blind treatment period. At Week0, patients will be randomly assigned to 1 of the following treatmentgroups: COMPOSITION 1a or 1b (approximately 2 g daily), COMPOSITION 1aor 1b (approximately 3 g daily), COMPOSITION 1a or 1b (approximately 4 gdaily), or placebo. The daily dose may be taken as either a single doseor distributed over two doses per day.

Approximately 80 patients per treatment group will be randomized in thisstudy. Stratification will be by baseline fasting TG level (≦750 mg/dLor >750 mg/dL, gender, and the use of statin therapy at randomization.During the double-blind treatment period, patients return to the site atWeek 4, Week 11, and Week 12 for efficacy and safety evaluations.

The primary objective of the study is to determine the efficacy ofCOMPOSITION 1 at a approximately 2 g daily dose, approximately 3 g dailydose and approximately 4 g daily dose, compared to placebo, in loweringfasting TG levels in patients with fasting TG levels ≧500 mg/dL and≦2000 mg/dL

The secondary and exploratory objectives of the study are as follows:

1. To determine the safety and tolerability of COMPOSITION 1a or 1b atapproximately 2 g daily, approximately 3 g daily and approximately 4 gdaily;

2. To determine the effect of COMPOSITION 1a or 1b on lipid profiles,including total cholesterol (TC), non-high-density lipoproteincholesterol (non-HDL-C) low-density lipoprotein cholesterol (LDL-C),high-density lipoprotein cholesterol (HDL-C), and very low-densitylipoprotein cholesterol (VLDL-C);

3. To determine the effect of COMPOSITION 1a or 1b on apolipoprotein A-I(apo A-I), apolipoprotein B (apo B), apo A-I/apo B ratio, lipoprotein(a)(Lp[a]), and lipoprotein-associated phospholipase A2 (Lp-PLA2);

4. To determine the effect of COMPOSITION 1a or 1b on low-densitylipoprotein (LDL) particle number and size, on oxidized LDL and onC-reactive protein (CRP).

5. To determine the effect of COMPOSITION 1a or 1b on intracellularadhesion molecule-1 (ICAM-1) vascular cell adhesion molecule 1(VCAM_(—)1), interleleukin-1 g (IL-1β), interleukin-2 (IL-2),interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10),interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18),tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β)and plasminogen activator inhibitor-1 (PAI-1);

6. To determine the effects of COMPOSITION 1a or 1b on nuclear factorkappa-light-chain-enhancer of activated B cells (NF-κB), vitronectinreceptor (αvβ3), glycoprotein IIb/IIIa (gpIIb/IIIa and other plateletand thrombogenic factors.

7. To determine the effects of COMPOSITION 1a or 1b on E-selectin,P-selectin, homocysteine, thromboxane B2 (TXB2), thromboxane A2 (TXA2),thromboxane B23 (TXB3), thromboxane A3 (TXA3), 2,3-dinor thromboxane B2,free fatty acids (FFA or NEFA), serum amyloid A1, serum amyloid A2,serum amyloid A3, serum amyloid A4, thiobarbituric acid (TBA) reactingmaterial, adiponectin (GBP-28), hemoglobin A1c (HbA1c), fasting insulin,fasting glucagon, fasting plasma glucose, fasting plasma fructosamine,macrophage colony stimulating factor (M-CSF) and granulocyte macrophagecolony stimulating factor (GM-CSF).

8. To determine the effects of COMPOSITION 1a or 1b on fibrinogen,fibrin D-dimer, platelet derived-microparticles, mean platelet volume(MPV), platelet subpopulations, adenosine diphosphate induced plateletaggregation, platelet endothelial cell adhesion molecule (PECAM-1),heart rate, and systolic and diastolic blood pressure.

9. To investigate the relationship between changes in fatty acidconcentrations (including EPA, DHA and DPA) in plasma and red blood cellmembranes and the reduction in fasting TG levels;

10. To investigate the relationship between changes in fatty acidconcentrations (including EPA, DHA and DPA) in plasma and red blood cellmembranes and the reduction in fasting TG levels.

The primary efficacy variable for the double-blind treatment period ispercent change in fasting TG from baseline to the Week 12 endpoint.

The secondary efficacy variable for the double-blind treatment periodincludes the following: Percent changes in fasting Non-HDL-C, LDL-C,VLDL-C, HDL-C, Lp-PLA2, and apo B from baseline to Week 12 endpoint.

Statistical methods for efficacy evaluations will be conducted on theintent-to-treat (ITT) and on the per-protocol population. Descriptivestatistics for the baseline and post-baseline measurements, the percentchanges, or changes from baseline are to be presented by treatment groupand by visit for all efficacy variables.

The primary and secondary efficacy analyses will be performed using ananalysis of covariance (ANCOVA) model with treatment, gender, and theuse of statin therapy at randomization as factors and baseline fastingTG value as a covariate.

In an alternate study design, this Study #3 is conducted with one ormore dose levels of COMPOSITION 2, 3, or 4 instead of COMPOSITION 1a or1b.

Example 38

The following describes a study (STUDY #4) to determine the effect ofcompositions of the present invention.

A Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 6- to12-Week Study to Evaluate the Efficacy and Safety of COMPOSITION 1a, 1b,2, 3, or 4 in Statin-Treated Patients With High Fasting TriglycerideLevels ≧200 mg/dL and 5499 mg/dL.

This multi-center study consists of a 4- to 6-week screening and washoutperiod (to include a diet and lifestyle stabilization period, and towash-out any non-statin/ezetimibe dyslipidemia medications), which alsoincludes a 2-3 week fasting triglyceride (TG) level qualifying period,followed by a 6- to 12-week double-blind treatment period. Patients onstatin therapy (with or without ezetimibe) at screening are evaluated bythe investigator as to whether this therapy does maintain low-densitylipoprotein (LDL) levels of ≧40 mg/dl and <100 mg/dl. At screening,statin therapy (with or without ezetimibe) is to be initiated, in thosepatients who are not on statin therapy in order to achieve LDL levels of≧40 mg/dl and <100 mg/dl. Dose(s) of statin therapy must be stable for≧4 weeks prior to the TG baseline qualifying measurements forrandomization.

The population for this study is men and women >18 years of age with abody mass index (BMI) ≦45 kg/m2. Patients on lipid-lowering therapy andpatients not on lipid-lowering therapy are eligible to enroll in thestudy. Patients had to have an average fasting TG level ≧200 mg/dL and≦499 mg/dL during the qualifying period to be eligible forrandomization.

After confirmation of qualifying fasting TG values, eligible patientswill enter a 6- to 12-week randomized, double-blind treatment period. AtWeek 0, patients will be randomly assigned to one of the followingtreatment groups: COMPOSITION 1a or 1b at an approximately 2 gram dailydose, COMPOSITION 1a or 1b at an approximately 3 gram daily dose,COMPOSITION 1a or 1b at an approximately 4 gram daily dose, or placebo.The daily dose may be taken as either a single dose or distributed overtwo doses per day.

Approximately 100 to 250 patients per treatment group will be randomizedin this study. Stratification will be by gender. During the double-blindtreatment period, patients will return to the site at Week 3 or 4, oneweek prior to the last week of randomized treatment period, and at theend or the randomized treatment period for efficacy and safetyevaluations.

The primary objective of the study is to determine the efficacy ofCOMPOSITION 1 at approximately 2 grams daily, approximately 3 gramsdaily and approximately 4 grams daily, compared to placebo, in loweringfasting TG levels in statin-treated patients with fasting TG levels ≧200mg/dL and ≦499 mg/dL.

The secondary and exploratory objectives of the study may include butare not limited to the following objectives:

1. To determine the safety and tolerability of COMPOSITION 1a or 1b atapproximately 2 g daily, approximately 3 g daily and approximately 4 gdaily;

2. To determine the effect of COMPOSITION 1a or 1b at on lipid profiles,including total cholesterol (TC), non-high-density lipoproteincholesterol (non-HDL-C) low-density lipoprotein cholesterol (LDL-C),high-density lipoprotein cholesterol (HDL-C), and very low-densitylipoprotein cholesterol (VLDL-C);

3. To determine the effect of COMPOSITION 1a or 1b on apolipoprotein A-I(apo A-I), apolipoprotein B (apo B), apo A-I/apo B ratio, lipoprotein(a)(Lp[a]), and lipoprotein-associated phospholipase A2 (Lp-PLA2);

4. To determine the effect of COMPOSITION 1a or 1b on low-densitylipoprotein (LDL) particle number and size, on oxidized LDL,high-sensitivity C-reactive protein (HSCRP). and on C-reactive protein(CRP).

5. To determine the effect of COMPOSITION 1a or 1b on intracellularadhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1(VCAM_(—)1), interleleukin-1β(IL-1β, interleukin-2 (IL-2), interleukin-6(IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12(IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), tumor necrosisfactor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β) and plasminogenactivator inhibitor-1 (PAI-1);

6. To determine the effects of COMPOSITION 1a or 1b on nuclear factorkappa-light-chain-enhancer of activated B cells (NF-κB), vitronectinreceptor (αvβ3), glycoprotein IIb/IIIa (gpIIb/IIIa and other plateletand thrombogenic factors.

7. To determine the effects of COMPOSITION 1a or 1b on E-selectin,P-selectin, homocysteine, thromboxane B2 (TXB2), thromboxane A2 (TXA2),thromboxane B23 (TXB3), thromboxane A3 (TXA3), 2,3-dinor thromboxane B2,free fatty acids (FFA or NEFA), serum amyloid A1, serum amyloid A2,serum amyloid A3, serum amyloid A4, thiobarbituric acid (TBA) reactingmaterial, adiponectin (GBP-28), hemoglobin A1c (HbA1c), fasting insulin,fasting glucagon, fasting plasma glucose, fasting plasma fructosamine,macrophage colony stimulating factor (M-CSF) and granulocyte macrophagecolony stimulating factor (GM-CSF).

8. To determine the effects of COMPOSITION 1a or 1b on fibrinogen,fibrin D-dimer, platelet derived-microparticles, mean platelet volume(MPV), platelet subpopulations, adenosine diphosphate induced plateletaggregation, platelet endothelial cell adhesion molecule (PECAM-1),heart rate, and systolic and diastolic blood pressure.

9. To determine the effects of COMPOSITION 1a or 1b on fatty acidconcentrations (including EPA, DHA and DPA) in plasma and red blood cellmembranes;

10. To investigate the relationship between changes in fatty acidconcentrations (including EPA, DHA and DPA) in plasma and red blood cellmembranes and the reduction in fasting TG levels.

The primary efficacy variable for the double-blind treatment period ispercent change in fasting TG from baseline to the Week 6 to 12 endpoint.

The secondary efficacy variable for the double-blind treatment periodinclude but are not limited to the following: Percent changes in fastingnon-HDL-C, LDL-C, VLDL-C, HDL-C, Lp-PLA2, and apo B from baseline toWeek 6 to 12 endpoint.

Statistical methods for efficacy evaluations will be conducted on theintent-to-treat (ITT) and on the per-protocol population. Descriptivestatistics for the baseline and post-baseline measurements, the percentchanges, or changes from baseline are to be presented by treatment groupand by visit for all efficacy variables.

The primary and secondary efficacy analyses will be performed using ananalysis of covariance (ANCOVA) model with treatment, gender, the typeof statin therapy and diagnosis of diabetes at randomization as factorsand baseline fasting TG value as a covariate.

In an alternate study design, this Study #4 is conducted with one ormore dose levels of COMPOSITION 2, 3, or 4 instead of COMPOSITION 1a or1b. In an alternative study design, Study #4 is conducted, enrollingpatients with a baseline triglyceride level of about 300 to 499 mg/dL orabout 350 too 400 mg/dL, instead of 200 to 499 mg/dL.

Example 39

The following describes a study (STUDY #5) to determine the effect ofcompositions of the present invention.

The impact on fasting triglyceride levels and other pharmacodynamicendpoints of one of COMPOSITION 1a, 1b, 2, 3, or 4 are evaluated versusa reference compound after administration under fasting or fedconditions in normal, mostly healthy volunteers in a standard, 4-waycross-over trial design format. VASCEPA®, EPANOVA™ LOVAZA®, or EPADEL®are used as a reference compound. A total of 48 subjects are separatedinto 2 groups of 24. Each subject serves as his or her own internalcontrol for comparison purposes under this 4-way crossover design.Inclusion criteria for tested subjects include volunteers between ages18-65, with a BMI of 30-35 (alternatively a BMI of 27-35) andtriglyceride levels less than 350 mg/dL, who consume no more than 1 fishmeal per week and who are not currently prescribed pharmaco-therapy forlowering triglycerides, including but not limited to fibrates, omega-3agents, and niacin. Volunteers on stable anti-hypertensive,anti-diabetic and thyroid therapy are allowed for consideration. Anyperson on stable statin therapy is considered if his or her triglyceridelevels are less than 350 mg/dL. However, the total composition ofsubjects in the study with this particular profile is limited to no morethan 30%.

Volunteers self-administering omega-3 non-prescription dietarysupplements are asked to refrain from their use 2 weeks prior to theinitiation of the study until study completion. Subjects using any othernon-steroidal anti-inflammatory agents other than acetaminophen areasked to abstain and switch to acetaminophen for relief of pain, or areexcluded from study consideration. Subjects are excluded if they receiveany type of hormone therapy, weight loss agents, HIV therapy,beta-blockers, or are diagnosed with known cardiovascular disease,including heart failure, arrhythmia, any incidence of acute coronarysyndrome, myocardial infarct, coronary artery bypass graft surgery,and/or angioplasty.

Study #5 Design

The effect of oral administration of the compounds tested in this studyis evaluated under fed versus fasting administration conditions, inorder to determine drug pharmacodynamics and effects on lipids.COMPOSITION 1a or 1b or the reference compound are dosed atapproximately 4 grams/day in the morning by administration of 4 capsulescontaining approximately 1 gram of each compound.

Compounds are given to volunteers following an overnight fast, withplasma samples obtained prior to dosing on day 1 and day 14 dosing.Volunteers are allowed access to water, and well-defined meals atcertain times. Afterwards, compound administration is stopped for a 2-4week washout period, and the groups are switched with respect to whichcompound they would receive, meaning that the group initially receivingCOMPOSITION 1a or 1b is switched to receive the reference compound, andvice versa. Following completion of the second 14-day dosing cycle,compound dosing is stopped for a 2-4-week washout period prior to theinitiation of the a similar cycle as above, now with COMPOSITION 1a or1b and the reference compound are administered together with a meal.

Baseline plasma levels of fasting serum triglycerides are determined onday 1 and just prior to initiation and completion of either the fastingor fed multi-dosing period. Additional lipid and other parameters (seebelow under “Results”) that are analyzed included total cholesterol,LDL, HDL, VLDL, non-HDL, and NEFA as previously described.

Effects on platelet function, such as clotting time and PAF-inducedaggregation are also determined. Standard physiological, plasma andurinary safety markers, including but not limited to electrolytes, ALT,AST, BUN, glucose, blood pressure, weight etc. are monitored inaccordance with standard good clinical trial guidelines.

Results

The results of the study show that COMPOSITION 1a or 1b has a betterfasting triglyceride lowering effect than the reference compound. Thiseffect is seen under fasting and/or fed administration conditions.Administration of COMPOSITION 1a or 1b have a beneficial effect, versusbaseline and versus the reference compound, on other lipid parameters(such as HDL cholesterol, total cholesterol, non-HDL cholesterol, VLDLcholesterol), on platelet function, and one or more of the following:apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), apo A-I/apo Bratio, lipoprotein(a) (Lp[a]), lipoprotein-associated phospholipase A2(Lp-PLA2), low density lipoprotein (LDL) particle number and size,oxidized LDL, C-reactive protein (CRP), high sensitivity C-reactiveprotein (HSCRP), intracellular adhesion molecule-1 (ICAM-1), E-selectin,P-selectin, vascular cell adhesion molecule 1 (VCAM-1) or cluster ofdifferentiation 106 (CD106), interleleukin-1β(IL-1β), interleukin-2(IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10(IL-10), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18(IL-18), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta(TNF-β), plasminogen activator inhibitor-1 (PAI-1), homocysteine,thromboxane B2 (TXB2), thromboxane A2 (TXA2), 2,3-dinor thromboxane B2,free fatty acids (FFA), serum amyloid A1, serum amyloid A2, serumamyloid A3, serum amyloid A4, thiobarbituric acid (TBA) reactingmaterial, adiponectin (GBP-28), hemoglobin A1c (HbA1c), macrophagecolony stimulating factor (M-CSF), granulocyte macrophage colonystimulating factor (GM-CSF), fibrinogen, fibrin D-dimer, plateletderived-microparticles, mean platelet volume (MPV), plateletsubpopulations, heart rate, systolic and diastolic blood pressure,nuclear factor kappa-light-chain enhancer of activated B cells (NF-κβ),adenosine diphosphate induced platelet aggregation, platelet endothelialcell adhesion molecule (PECAM-1), vitronectin receptor (α_(v)β_(v)), andglycoprotein IIb/IIIa (gpIIIb/IIIa). This effect is more beneficial thanthat observed with VASCEPA®. Administration of COMPOSITION 1 has abeneficial impact, or a minimal impact, or no impact, on other non-HDLlipid parameters, such as LDL cholesterol versus baseline and thereference compound. In an alternate study design, this Study #5 isconducted with a certain dose level of COMPOSITION 2, 3, pr 4 instead ofCOMPOSITION 1a or 1b.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

-   1. A fatty acid composition comprising at least 50% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   2. A fatty acid composition comprising at least 60% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   3. A fatty acid composition comprising at least 70% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   4. A fatty acid composition comprising at least 75% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   5. A fatty acid composition comprising at least 80% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   6. A fatty acid composition comprising at least 85% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   7. A fatty acid composition comprising at least 90% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   8. A fatty acid composition comprising at least 95% omega-3-fatty    acids, salts or derivatives thereof, while comprising    eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid    (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.-   9. A composition according to one of the preferred embodiments 1    through 8, comprising at least 2% docosapentaenoic acid (DPA;    C22:5-n3).-   10. A composition according to one of the preferred embodiments 1    through 8, comprising at least 4% docosapentaenoic acid (DPA;    C22:5-n3).-   11. A composition according to one of the preferred embodiments 1    through 8, comprising at least 5% docosapentaenoic acid (DPA;    C22:5-n3).-   12. A composition according to one of the preferred embodiments 1    through 8, comprising at least 6% docosapentaenoic acid (DPA;    C22:5-n3).-   13. A composition according to one of the preferred embodiments 1    through 8, comprising at least 7% docosapentaenoic acid (DPA;    C22:5-n3).-   14. A composition according to one of the preferred embodiments 1    through 8, comprising at least 8% docosapentaenoic acid (DPA;    C22:5-n3).-   15. A composition according to one of the preferred embodiments 1    through 8, comprising at least 10% docosapentaenoic acid (DPA;    C22:5-n3).-   16. A composition according to one of the preferred embodiments 1    through 8, comprising at least 12% docosapentaenoic acid (DPA;    C22:5-n3).-   17. A composition according to one of the preferred embodiments 1    through 8, comprising at least 15% docosapentaenoic acid (DPA;    C22:5-n3).-   18. A composition according to one of the preferred embodiments 1    through 17, comprising no more than 95% EPA.-   19. A composition according to one of the preferred embodiments 1    through 17, comprising no more than 10% omega-6 fatty acids.-   20. A composition according to one of the preferred embodiments 1    through 17, comprising no more than 7% omega-6 fatty acids.-   21. A composition according to one of the preferred embodiments 1    through 17, comprising no more than 5% omega-6 fatty acids.-   22. A composition according to one of the preferred embodiments 1    through 17, comprising no more than 3% omega-6 fatty acids.-   23. A composition according to one of the preferred embodiments 1    through 22, comprising no more than 5% arachidonic acid (C22:4-n6).-   24. A composition according to one of the preferred embodiments 1    through 22, comprising no more than 4% arachidonic acid (C22:4-n6).-   25. A composition according to one of the preferred embodiments 1    through 22, comprising no more than 3% arachidonic acid (C22:4-n6).-   26. A composition according to one of the preferred embodiments 1    through 22, comprising no more than 2% arachidonic acid (C22:4-n6).-   27. A composition according to one of the preferred embodiments 1    through 22, comprising no more than 1% arachidonic acid (C22:4-n6).-   28. A composition according to one of the preferred embodiments 1    through 27, also comprising heneicosapentaenoic acid (C21:5-n3).-   29. A composition according to one of the preferred embodiments 1    through 27, comprising at least 0.01% heneicosapentaenoic acid    (C21:5-n3).-   30. A composition according to one of the preferred embodiments 1    through 27, comprising at least 0.1% heneicosapentaenoic acid    (C21:5-n3).-   31. A composition according to one of the preferred embodiments 1    through 27, comprising at least 0.3% heneicosapentaenoic acid    (C21:5-n3).-   32. A composition according to one of the preferred embodiments 1    through 27, comprising at least 0.5% heneicosapentaenoic acid    (C21:5-n3).-   33. A composition according to one of the preferred embodiments 1    through 27, comprising at least 1% heneicosapentaenoic acid    (C21:5-n3).-   34. A composition according to one of the preferred embodiments 1    through 27, comprising at least 2% heneicosapentaenoic acid    (C21:5-n3).-   35. A composition according to one of the preferred embodiments 1    through 27, comprising at least 3% heneicosapentaenoic acid    (C21:5-n3).-   36. A composition according to one of the preferred embodiments 1    through 27, comprising at least 4% heneicosapentaenoic acid    (C21:5-n3).-   37. A composition according to one of the preferred embodiments 1    through 27, comprising at least 5% heneicosapentaenoic acid    (C21:5-n3).-   38. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 5% omega-3 fatty acids that are    not omega-3-pentaenoic acids.-   39. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 4% omega-3 fatty acids that are    not omega-3-pentaenoic acids.-   40. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 3% omega-3 fatty acids that are    not omega-3-pentaenoic acids.-   41. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 2% omega-3 fatty acids that are    not omega-3-pentaenoic acids.-   42. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 1.5% omega-3 fatty acids that    are not omega-3-pentaenoic acids.-   43. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 1.25% omega-3 fatty acids that    are not omega-3-pentaenoic acids.-   44. A composition according to one of the preferred embodiments 1    through 37, comprising no more than 1% omega-3 fatty acids that are    not omega-3-pentaenoic acids.-   45. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 99:1 and 1:99.-   46. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 60:1 and 1:60.-   47. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 50:1 and 1:10.-   48. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 1:3.-   49. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 1:2.-   50. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 1:1.-   51. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 30:1 and 1:1.-   52. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 20:1 and 1:1.-   53. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 10:1 and 1:1.-   54. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 5:1 and 1:1.-   55. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 10:1 and 2:1.-   56. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 20:1 and 2:1.-   57. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 30:1 and 2:1.-   58. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 2:1.-   59. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 50:1 and 2:1.-   60. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 10:1 and 3:1.-   61. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 20:1 and 3:1.-   62. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 30:1 and 3:1.-   63. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 3:1.-   64. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 50:1 and 3:1.-   65. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 60:1 and 3:1.-   66. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 10:1 and 5:1.-   67. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 20:1 and 5:1.-   68. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 30:1 and 5:1.-   69. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 5:1.-   70. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 50:1 and 5:1.-   71. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 60:1 and 5:1.-   72. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 20:1 and 10:1.-   73. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 30:1 and 10:1.-   74. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 40:1 and 10:1.-   75. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 50:1 and 10:1.-   76. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 60:1 and 10:1.-   77. A composition according to one of the preferred embodiments 1    through 44, wherein the EPA:DPA ratio is between 100:1 and 10:1.-   78. A composition according to one of the preferred embodiments 1    through 44, comprising between 55% and 95% EPA.-   79. A composition according to one of the preferred embodiments 1    through 44, comprising between 60% and 95% EPA.-   80. A composition according to one of the preferred embodiments 1    through 44, comprising between 65% and 95% EPA.-   81. A composition according to one of the preferred embodiments 1    through 44, comprising between 70% and 95% EPA.-   82. A composition according to one of the preferred embodiments 1    through 44, comprising between 75% and 95% EPA.-   83. A composition according to one of the preferred embodiments 1    through 44, comprising between 80% and 95% EPA.-   84. A composition according to one of the preferred embodiments 1    through 44, comprising between 85% and 95% EPA.-   85. A composition according to one of the preferred embodiments 1    through 44, comprising between 90% and 95% EPA.-   86. A composition according to one of the preferred embodiments 1    through 44, comprising between 1% and 3% DPA.-   87. A composition according to one of the preferred embodiments 1    through 44, comprising between 1% and 5% DPA.-   88. A composition according to one of the preferred embodiments 1    through 44, comprising between 2% and 10% DPA.-   89. A composition according to one of the preferred embodiments 1    through 44, comprising between 3% and 20% DPA.-   90. A composition according to one of the preferred embodiments 1    through 44, comprising between 3% and 30% DPA.-   91. A composition according to one of the preferred embodiments 1    through 44, comprising between 3% and 50% DPA.-   92. A composition according to one of the preferred embodiments 1    through 44, comprising between 3% and 75% DPA.-   93. A composition according to one of the preferred embodiments 1    through 44, comprising between 3% and 90% DPA.-   94. A fatty acid composition according to one of the preferred    embodiments 1 through 93, in which the fatty acids are present as    ethyl esters.-   95. A fatty acid composition according to one of the preferred    embodiments 1 through 93, in which the fatty acids are present as    free fatty acids.-   96. A fatty acid composition according to one of the preferred    embodiments 1 through 93, in which the fatty acids are present as    esters in di-glyceride form.-   97. A fatty acid composition according to one of the preferred    embodiments 1 through 93, in which the fatty acids are present as    esters in triglyceride form.-   98. A fatty acid composition according to one of the preferred    embodiments 94 through 97, also comprising a suitable anti-oxidant    in a concentration sufficient to protect the fatty acids of the    composition from oxidation.-   99. A pharmaceutically suitable formulation comprising one of the    compositions according to preferred embodiments 94 through 98, in    which the amount of eicosapentaenoic acid plus docosapentaenoic acid    is present in an amount between 100 and 10,000 mg.-   100. A pharmaceutically suitable formulation or dosage form    comprising one of the compositions according to preferred    embodiments 94 through 98, in which the amount of eicosapentaenoic    acid plus docosapentaenoic acid is present in an amount between 250    and 1,250 mg.-   101. A pharmaceutically suitable formulation or dosage form    comprising one of the compositions according to preferred    embodiments 94 through 98, in which the amount of eicosapentaenoic    acid plus docosapentaenoic acid is present in an amount between 500    and 1,100 mg.-   102. A pharmaceutically suitable formulation or dosage form    comprising one of the compositions according to preferred    embodiments 94 through 98, in which the amount of eicosapentaenoic    acid plus docosapentaenoic acid is present in an amount between 100    and 10,000 mg.-   103. A method of administration or treatment to a subject of a    formulation or dosage form according to one of the preferred    embodiments 94 through 102 at a daily dose between 100 and 10,000    mg.-   104. A method of administration or treatment to a subject of a    formulation or dosage form according to one of the preferred    embodiments 94 through 102 at a daily dose between 500 and 5,000 mg.-   105. A method of administration or treatment to a subject of a    formulation or dosage form according to one of the preferred    embodiments 94 through 102 at a daily dose between 1,500 and 4,100    mg.-   106. A method of treatment according to preferred e embodiments 103    through 105, in which the subject is a patient diagnosed with very    high triglycerides (equal or more than 500 mg/dL).-   107. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with high    triglycerides (equal to or more than 200 mg/dL but less than 500    mg/dL).-   108. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient already undergoing    treatment with a statin and then diagnosed with high triglycerides    (equal to or more than 200 mg/dL but less than 500 mg/dL).-   109. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and LDL-cholesterol equal to or    more than 190 mg/dL.-   110. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and LDL-cholesterol equal to or    more than 190 mg/dL.-   111. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and non-HDL-cholesterol equal to    or more than 200 mg/dL.-   112. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and non-HDL-cholesterol equal to    or more than 200 mg/dL.-   113. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and LDL-cholesterol equal to or    more than 160 mg/dL.-   114. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and LDL-cholesterol equal to or    more than 160 mg/dL.-   115. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and non-HDL-cholesterol equal to    or more than 160 mg/dL.-   116. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and non-HDL-cholesterol equal to    or more than 160 mg/dL.-   117. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and LDL-cholesterol equal to or    more than 130 mg/dL.-   118. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and LDL-cholesterol equal to or    more than 130 mg/dL.-   119. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 200-499 mg/dL and non-HDL-cholesterol equal to    or more than 130 mg/dL.-   120. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with mixed    dyslipidemia with TG 300-700 mg/dL and non-HDL-cholesterol equal to    or more than 130 mg/dL.-   121. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed/assessed to    be at substantially elevated risk for cardiovascular events.-   122. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with    diabetes.-   123. A method of treatment according to preferred embodiments 103    through 105, in which the subject is a patient diagnosed with    pre-diabetes or metabolic syndrome.-   124. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma triglyceride levels.-   125. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma triglyceride levels    while not significantly increasing blood, serum or plasma    LDL-cholesterol levels.-   126. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma total-cholesterol    levels.-   127. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma non-HDL-cholesterol    levels.-   128. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma LDL-cholesterol    levels.-   129. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma VLDL-cholesterol    levels.-   130. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma VLDL-cholesterol    levels while not significantly increasing blood, serum or plasma    LDL-cholesterol levels.-   131. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma apo-B levels.-   132. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma apo-C-III levels.-   133. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma LP-PLA2 levels.-   134. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of blood, serum or plasma hs-CRP levels.-   135. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant increase of blood, serum or plasma HDL-cholesterol    levels.-   136. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant increase of blood, serum or plasma apo-A levels.-   137. A method of treatment according to one of the preferred    embodiments 103 through 123, in which the treatment results in    significant reduction of the risk of suffering certain    cardiovascular events.-   138. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 8 hours or less-   139. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 6 hours or less-   140. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 5 hours or less-   141. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 4 hours or less-   142. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 8 hours or less-   143. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 6 hours or less-   144. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 5 hours or less-   145. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in a Tmax of 4 hours or less-   146. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Tmax less than the EPA+DPA+DHA Tmax    for LOVAZA® under the same administration conditions-   147. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Tmax less than the EPA+DPA+DHA Tmax    for LOVAZA® under the same administration conditions-   148. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Tmax less than the EPA+DPA Tmax for    AMR101 under the same administration conditions-   149. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Tmax less than the EPA+DPA Tmax for    AMR101 under the same administration conditions-   150. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an Total Omega-3 FA Tmax less than the Total    Omega-3 FA Tmax for LOVAZA® under the same administration conditions-   151. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an Total Omega-3 FA Tmax less than the Total    Omega-3 FA Tmax for LOVAZA® under the same administration conditions-   152. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an Total Omega-3 FA Tmax less than the Total    Omega-3 FA Tmax for AMR101 under the same administration conditions-   153. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an Total Omega-3 FA Tmax less than the Total    Omega-3 FA Tmax for AMR101 under the same administration conditions-   154. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 110% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   155. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 120% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   156. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 130% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   157. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 140% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   158. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   159. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   160. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 200% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   161. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 300% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   162. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 400% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   163. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 500% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   164. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 600% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   165. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   166. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 200% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   167. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 300% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   168. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 400% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   169. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 500% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   170. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 600% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   171. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 700% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    LOVAZA® under the same administration conditions-   172. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 110% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   173. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 120% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   174. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 130% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   175. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 140% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   176. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 150% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   177. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 150% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   178. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 200% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   179. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 300% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   180. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 400% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   181. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 500% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   182. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 600% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   183. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 150% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   184. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 200% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   185. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 300% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   186. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 400% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   187. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 500% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   188. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 600% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   189. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 700% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    LOVAZA® under the same administration conditions-   190. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 110% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   191. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 120% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   192. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 130% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   193. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 140% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   194. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   195. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   196. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 200% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   197. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 300% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   198. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 400% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   199. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 500% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   200. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 600% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   201. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   202. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 200% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   203. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 300% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   204. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 400% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   205. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 500% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   206. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 600% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   207. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA Cmax or Total Omega-3 FA Cmax of at    least 700% of the EPA+DPA Cmax or Total Omega-3 FA Cmax for AMR101    under the same administration conditions-   208. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    110% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   209. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    120% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   210. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    130% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   211. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    140% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   212. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    150% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   213. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    150% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   214. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    200% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   215. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    300% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   216. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    400% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   217. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    500% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   218. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    600% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   219. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    150% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   220. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    200% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   221. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    300% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   222. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    400% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   223. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    500% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   224. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    600% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   225. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA AUC or Total Omega-3 FA AUC of at least    700% of the EPA+DPA AUC or Total Omega-3 FA AUC for AMR101 under the    same administration conditions-   226. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 100% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   227. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 105% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   228. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 110% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   229. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 120% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   230. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 130% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   231. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 140% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   232. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 100% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   233. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 105% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   234. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 110% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   235. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 120% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   236. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 130% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   237. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 140% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   238. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 100% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   239. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 105% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   240. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 110% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   241. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 120% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   242. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 130% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   243. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 140% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   244. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax of at    least 150% of the EPA+DPA+DHA Cmax or Total Omega-3 FA Cmax for    EPANOVA™ under the same administration conditions-   245. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 100% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   246. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 105% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   247. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 110% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   248. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 120% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   249. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 130% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   250. A method of administration or treatment under high fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 140% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   251. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 100% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   252. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 105% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   253. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 110% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   254. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 120% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   255. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 130% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   256. A method of administration or treatment under low fat meal    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 140% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   257. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 100% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   258. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 105% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   259. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 110% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   260. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 120% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   261. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 130% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   262. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 140% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions-   263. A method of administration or treatment under fasting    conditions according to one of the preferred embodiments 103 through    105 resulting in an EPA+DPA+DHA AUC or Total Omega-3 FA AUC of at    least 150% of the EPA+DPA+DHA AUC or Total Omega-3 FA AUC for    EPANOVA™ under the same administration conditions.-   264. The composition of claim 1, wherein the ratio of EPA to DPA    (EPA:DPA) is between 15:1 to 8:1.-   265. An orally administrable composition comprising fatty acids,    wherein at least 50% by weight of the fatty acids comprise    omega-3-pentaenoic acids, salts, esters, or derivatives thereof,    wherein the composition comprises eicosapentaenoic acid (EPA),    docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), and    wherein the ratio of DHA to EPA (DHA:EPA) is less than 1:20, and    wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1.

What is claimed:
 1. A method of reducing triglyceride levels in asubject from a baseline triglyceride level, comprising administering tothe subject a composition comprising fatty acids, wherein at least 50%by weight of the fatty acids comprise omega-3 fatty acids, salts,esters, or derivatives thereof, wherein the omega-3 fatty acids compriseeicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) and whereinthe ratio of docosahexaenoic acid to DHA to EPA (DHA:EPA) is less than1:10, and wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1. 2.The method of claim 1, wherein the ratio of DHA:EPA is less than 1:20.3. The method of claim 1, wherein the ratio of DHA:DPA is less than 1:1.4. The method of claim 1, wherein the ratio of EPA to DPA (EPA:DPA) isbetween 30:1 and 1:1.
 5. The method of claim 1, wherein the compositioncomprises DHA in an amount less than 5% of the total amount of fattyacids.
 6. The method of claim 1, wherein the composition comprises EPAin an amount between about 80% and about 90% of the total amount offatty acids.
 7. The method of claim 1, wherein the composition comprisesDPA in an amount between about 5% and about 15% of the total amount offatty acids.
 8. The method of claim 1, wherein the composition comprisesDPA free fatty acid or a salt, ester or derivative of DPA.
 9. The methodof claim 1, wherein composition comprises EPA free fatty acid or a salt,ester or derivative of EPA.
 10. The method of claim 1, wherein thecomposition comprises eicosapentaenoic acid (EPA) in an amount betweenabout 750 mg/g to about 950 mg/g, and wherein the composition comprisesno more than 5% DHA of the total amount of fatty acids, and and whereinthe ratio of DHA:DPA is 1:1 or lower.
 11. The method of claim 1, whereinthe composition comprises eicosapentaenoic acid (EPA) in an amountbetween about 800 mg/g to about 900 mg/g, and wherein the compositioncomprises no more than 5% DHA of the total amount of fatty acids, andand wherein the ratio of DHA:DPA is 1:1 or lower.
 12. The method ofclaim 1, wherein the composition comprises eicosapentaenoic acid (EPA)in an amount between about 830 mg/g to about 870 mg/g, and wherein thecomposition comprises no more than 5% DHA of the total amount of fattyacids, and and wherein the ratio of DHA:DPA is 1:1 or lower.
 13. Themethod of claim 1, wherein the composition comprises docosapentaenoicacid (DPA) is an amount between about 60 mg/g to about 120 mg/g.
 14. Themethod of claim 1, wherein the composition comprises docosapentaenoicacid (DPA) is an amount between about 70 mg/g to about 100 mg/g.
 15. Amethod of reducing triglyceride levels in a subject from a baselinetriglyceride level, comprising administering to the subject acomposition comprising: eicosapentaenoic acid (EPA) in an amount betweenabout 70% to about 95% of the total amount of fatty acids anddocosapentaenoic acid (DPA), wherein the composition comprises no morethan 5% docosahexaenoic acid (DHA) of the total amount of fatty acids,and wherein the ratio of DHA:DPA is 1:1 or lower.
 16. The method ofclaim 15, wherein the composition comprises eicosapentaenoic acid (EPA)in an amount between about 80% to about 90% of the total amount of fattyacids.
 17. The method of 15, wherein the composition compriseseicosapentaenoic acid (EPA) in an amount between about 82% to about 88%of the total amount of fatty acids.
 18. The method of 15, wherein thecomposition comprises docosapentaenoic acid (DPA) in amount betweenabout 5% and about 15% of the total amount of fatty acids.
 19. Themethod of 15, wherein the composition comprises docosapentaenoic acid(DPA) in an amount between about 6% to about 12% of the total amount offatty acids.
 20. The method of claim 15, wherein the compositioncomprises EPA free fatty acid or a salt, ester or derivative of EPA. 21.A method of reducing triglyceride levels in a subject from a baselinetriglyceride level, comprising administering to the subject acomposition comprising eicosapentaenoic acid (EPA) in a daily dosageamount of between about 1000 mg to about 5000 mg, and further comprisingdocosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), wherein thecomposition comprises no more than 5% DHA of the total amount of fattyacids, and wherein the ratio of DHA:DPA is 1:1 or lower.
 22. The methodof claim 21, wherein the composition comprises eicosapentaenoic acid(EPA) in a daily dosage amount selected from the group consisting of:about 1735 mg to about 1855 mg, about 2520 mg to about 2780 mg, andabout 3360 mg to about 3710 mg.
 23. The method of claim 21, wherein thecomposition comprises eicosapentaenoic acid (EPA) in a daily dosageamount selected from the group consisting of: about 1750 mg to about1950 mg, about 1800 mg to about 2000 mg about 2650 mg to about 2950 mg,and about 3500 mg to about 3900 mg.
 24. The method of claim 21, whereinthe composition comprises eicosapentaenoic acid (EPA) in daily dosageamount selected from the group consisting of: about 1900 mg to about2100 mg, about 2700 mg to about 3300 mg, and about 3700 mg to about 4300mg.
 25. The method of claim 21, wherein the composition comprises EPAfree fatty acid or a salt, ester or derivative of EPA.
 26. The method ofclaim 21, wherein the composition comprises DPA free fatty acid or asalt, ester or derivative of DPA.
 27. A method of reducing a lipidparameter level in a subject from a baseline lipid parameter level,wherein the lipid parameter is selected from the group consisting of:total cholesterol, VLDL-cholesterol, apolipoprotein B (apo B), andapolipoprotein C-III (apo C-III), comprising administering to thesubject a composition comprising fatty acids, wherein at least 50% byweight of the fatty acids comprise omega-3 fatty acids, salts, esters,or derivatives thereof, wherein the omega-3 fatty acids compriseeicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and wherein theratio of docosahexaenoic acid to DHA to EPA (DHA:EPA) is less than 1:10,and wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1.
 28. Themethod of claim 27, wherein the composition comprises EPA in an amountbetween about 80% and about 90% of the total amount of fatty acids. 29.The method of claim 27, wherein the composition comprises DHA in anamount less than 5% of the total amount of fatty acids.
 30. The methodof claim 27, wherein the composition comprises DPA in an amount betweenabout 5% and about 15% of the total amount of fatty acids.